Revised: 20 May 2013

Committees

Minutes of the 124th Medicines Adverse Reactions Committee Meeting - 15 December 2005

Preface:

In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.

Names of individuals have also been deleted where that person’s contribution is not in the public domain, or will not shortly be so. For example, the names of those to be approached to write an article are deleted, but the names of those who have contributed to a draft article are not usually deleted. In addition, names are not usually deleted when a contribution has been made in an official capacity.

The material listed as being considered on an issue is not intended to be exhaustive.

The recommendations of the Committee are in bold typeface.

Note regarding minute item 2.1.3, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk:

On 4 February 2006, subsequent to the MARC meeting, the Lancet published a full retraction of the article by Sudbo et al, which was reviewed by the MARC for minute item 2.1.3. Medsafe considers that the Committee's recommendation on this issue does not need to be rescinded. See minute item 2.1.3 for further details.

Minutes:

TABLE OF CONTENTS

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

INVITED GUESTS AND EXPERTS

1. MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies
1.2 Minutes of the 123^rd MARC Meeting

1.2.1 Report to the Minister's Delegate

1.3 Dates of Future MARC Meetings

1.4 Potential Conflicts of Interest

1.5 Prescriber Update

1.5.1 Prescriber Update. Vol. 26; No. 1. June 2005.
1.5.2 Schedule of planned Prescriber Update articles.

2. ACTIONS ARISING

2.1 Report on Actions Arising from the 123^rd MARC Meeting, 9 June 2005

2.1.1 Schedule of Planned Prescriber Update Articles
2.1.2 Article for Peer-Review - Methadone and QT Interval Prolongation
2.1.3 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk
2.1.4 Bisphosphonates and Osteonecrosis of the Jaw (ONJ)
2.1.5 Review of Adverse Reactions of Current Concern
2.1.6 Review of Watching Briefs
2.1.7 Paroxetine and Use in Pregnancy
2.1.8 Chlorpromazine and Neuroleptic Malignant Syndrome (CARM case 64723)
2.1.9 Atorvastatin and Aggressive Reaction (CARM case 67166)
2.1.10 Other CARM Case Reports
2.1.11 Analysis of IMMP Events Reported for Sibutramine
2.1.12 Sibutramine and Bruising

2.2 REPORT ON ACTIONS ARISING FROM PREVIOUS MEETINGS OF THE MARC

2.2.1 MARC Membership – Vacant Positions
2.2.2 COX-2 Inhibitors and Cardiovascular Safety
2.2.3 Valdecoxib and Serious Cutaneous Adverse Reactions (SCARs)
2.2.4 Methotrexate, Leflunomide and Respiratory Adverse Effects (CARM cases 63532 and 64391)
2.2.5 Colchicine Dosage
2.2.6 Salamol Inhaler – Device Failure Issues
2.2.7 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose
2.2.8 Phenytoin, Fluorouracil and Ataxia, Dizziness, Drug Level Increased (CARM case 62606)
2.2.9 Analysis of IMMP Events Reported for Risperidone
2.2.10 Pergolide and Cardiac Valvulopathy
2.2.11 Domperidone and the Risk of QT Prolongation
2.2.12 Low Molecular Weight Heparins (LMWHs) in Renal Impairment
2.2.13 Sodium Valproate and Pancreatitis (CARM case 63175)
2.2.14 Mometasone and Rosacea (CARM case 62554)
2.2.15 Miconazole, Warfarin Interaction and Haematuria, Prothrombin Increased (CARM case 63753)
2.2.16 Pimecrolimus Application Site Reactions

3. PHARMACOVIGILANCE ISSUES

3.1 Review of Watching Briefs

3.1.1 Bupropion and Cardiovascular Adverse Effects
3.1.2 Selective Serotonin Reuptake Inhibitors (SSRIs) and Haemorrhage
3.1.3 COX-2 Inhibitors/Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Impaired Fracture Healing
3.1.4 Rosiglitazone and Pancreatitis
3.1.5 Selective Serotonin Reuptake Inhibitors (SSRIs) and Withdrawal Reactions
3.1.6 COX-2 Inhibitors and Cardiovascular Adverse Events
3.1.7 Rosiglitazone and Cardiac Failure
3.1.8 Topiramate and Serious Psychiatric Reactions
3.1.9 Rosiglitazone and Lipid Abnormalities
3.1.10 DTaP/IPV/Hep B/HiB Vaccine and Sudden Death
3.1.11 Cephazolin and Pancreatitis
3.1.12 MMR Vaccine and Arthritis
3.1.13 Domperidone and QT Prolongation
3.1.14 Over-the-Counter (OTC) Medication Errors
3.1.15 Pergolide and Cardiac Valvulopathy
3.1.16 Valproate and Foetal Abnormalities

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 Centre for Adverse Reactions Monitoring (CARM) Case Reports

4.1.1 Deaths
4.1.2 Alternative Medicines
4.1.3 Antibacterials
4.1.4 Antihaemorrhagics
4.1.5 Anti-inflammatories
4.1.6 Antineoplastics
4.1.7 Cardiovascular Medicines
4.1.8 Contrast media
4.1.9 Drug Interactions
4.1.10 Hormones
4.1.11 Immunosuppressives
4.1.12 Vaccines
4.1.13 Other Reports

4.2 Pharmacovigilance Issues Arising From Reports to CARM

4.2.1 Lipid-Lowering Agents and Psychiatric Adverse Reactions
4.2.2 Ezetimibe and Muscle Disorders

4.3 Intensive Vaccines Monitoring Programme (IVMP) - Meningococcal B Vaccine

4.3.1 MeNZB Adverse Event Assessments

4.4 Quarterly Report from CARM as at 30 SEPTEMBER 2005

5. PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

5.1 NSAIDS/COX-2 INHIBITORS
5.2 ATYPICAL ANTIPSYCHOTICS IN DEMENTIA
5.3 BETA-BLOCKERS
5.4 OTHERS

6. NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

7. INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 Australia

7.2 Canada

8. SUMMARY OF CASE REPORTS CONSIDERED BY MARC (1997-2005)

9. OTHER BUSINESS

9.1 Oral Presentations on WHO and ISoP Pharmacovigilance Conferences
9.2 Update on the Australia New Zealand Therapeutic Products Authority (Formerly Joint Trans-Tasman Agency)

---

Minutes:

The one hundred and twenty-fourth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 15 December 2005 at the De Havilland room, Wellington Airport Conference Centre, Wellington, New Zealand. The meeting commenced at 0900 and closed at 1620.

marc members present

Dr M. Rademaker (Acting Chair)
Dr H. Kingston
Dr F. McClure
Prof P. Ellis
Dr M. Tatley
Dr S. Sime

marc secretariat present

Dr S. Jessamine (Principal Technical Specialist, Medicines Regulation and Pharmacovigilance, Medsafe)
Ms S. Von Afehlt (Senior Pharmacy Advisor/Editor of Prescriber Update, Medsafe)
Dr K. Moses (Pharmacovigilance Advisor/MARC Secretary, Medsafe)

invited guestS AND EXPERTs

Dr R Savage (New Zealand Pharmacovigilance Centre)
Miss A. Tan (Professional Officer, Adverse Drug Reaction Unit, Australian Therapeutic Goods Administration)

Dr J. O’Hallahan (Director - Meningococcal Vaccine Strategy, Ministry of Health) and Ms A. McNicholas (Senior Advisor, Ministry of Health) made a presentation to the Committee on the meningococcal B vaccine safety monitoring programme.

1.  Matters of Administration

1.1 Welcome and Apologies

Apologies had been received from Assoc. Prof. T. Maling (Chair) and Prof. D. Skegg. Prof Maling provided written comments on some issues, which were tabled at the meeting.

Dr McClure arrived at the meeting at 10:30am due to transport difficulties, therefore, the meeting was inquorate until this time. The recommendations made by the Committee prior to 10:30am (relevant to minute items 1.1, 1.3 to 1.5, 3.1 and 3.1.1 to 3.1.7) were communicated to Dr McClure upon her arrival, who agreed that they were appropriate, whereupon a motion was passed to confirm those recommendations.

1.2 Minutes of the 123^rd MARC Meeting

Regarding minute item 1.4, Potential Conflicts of Interest, “Dr Rademaker declared that his previous involvement in clinical trials had been completed” was amended to read, “Dr Rademaker declared that his previous involvement in clinical trials had not started”. The Secretary agreed to make this change to the minutes. The members agreed that the minutes of the 123rd MARC meeting were otherwise a true and accurate record of the meeting. The Acting Chair subsequently ratified the minutes

1.2.1 Report to the Minister's Delegate

The Committee noted that one recommendation from the September 2005 MARC meeting, regarding minute item 1.5.2 Pergolide and Cardiac Valvulopathy, had been rejected by the Minister’s Delegate on the advice of Medsafe (see minute item 2.1.1). The Committee supported this decision.

1.3 Dates of Future MARC Meetings

The date for the next MARC meeting was confirmed as being Thursday 16 March 2006. The subsequent MARC meetings were scheduled for 15 June 2006, 14 September 2006 and 14 December 2006.

1.4 Potential Conflicts of Interest

Committee members, including Prof. Maling, submitted their Conflict of Interest Declaration forms to the Secretary. The Acting Chair reminded MARC members that, in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.

Dr Rademaker declared that he had received fees for consulting with investigators regarding a trial of low dose isotretinoin, being organised by Douglas Pharmaceuticals. This potential conflict of interest was not considered to influence the discussions or decisions of the Committee.

1.5 Prescriber Update

1.5.1 Prescriber Update. Vol. 26; No. 2. December 2005.

Discussion

The Committee complimented the Medsafe Editorial Team on the December 2005 edition of Prescriber Update.

1.5.2 Schedule of planned Prescriber Update articles.

Discussion

See minute items 2.2.10 and 2.2.16 for discussion on two Prescriber Update articles to be rescinded. The Committee noted that many articles in the schedule had been published in the December 2005 edition of Prescriber Update, and others were being progressed.

2. actions arising

2.1 Report on Actions Arising from the 122^nd MARC Meeting, 15 September 2005

Please refer to the minutes of the 122^nd MARC meeting, held on 9 June 2005, available on the Medsafe website at www.medsafe.govt.nz/Profs/adverse/Minutes123.htm for background information surrounding these issues.

2.1.1 Schedule of Planned Prescriber Update Articles

September 2005 minute item 1.5.2

Issue

The Committee recommended that the Chair should seek the advice of cardiologists regarding the issue of cardiac monitoring for patients prescribed pergolide.

The Committee recommended that the planned Prescriber Update article on ‘Cutaneous reactions: top 10 causally associated medicines’ should be replaced with an article on the medicines that cause serious cutaneous adverse reactions (SCARs).

Outcome

In November 2005, Medsafe requested that the Minister’s Delegate reject the MARC’s recommendation that "the Chair should seek the advice of cardiologists regarding the issue of cardiac monitoring for patients prescribed pergolide" for the following reasons.

• The Committee agreed at their December 2004 meeting that the monitoring requirements recommended by the sponsor were appropriate.
• Medsafe cannot disseminate advice differing from that in the product data sheet unless there is good evidence for doing so.

Dr Rademaker authored an article on the medicines that cause serious cutaneous adverse reactions (SCARs), which was published in the December 2005 issue of Prescriber Update.

Discussion

The Committee noted the recommendation rejected by the Minister’s Delegate on the advice of Medsafe, and supported that decision. See minute item 2.2.10 for further outcomes on pergolide and cardiac valvulopathy, and minute item 3.1.15 for a review of the watching brief held on the same issue.

2.1.2 Article for Peer-Review - Methadone and QT Interval Prolongation

September 2005 minute item 1.5.3

Issue

The Committee recommended that Medsafe should consider making the following changes to the Prescriber Update article on methadone and QT prolongation:

• The opening paragraph should contain the value of QTc interval prolongation.
• The risk factors for QTc prolongation should be more extensively detailed, perhaps in table format.
• There should be mention of The University of Arizona Center for Education and Research on Therapeutics web site, ‘Drugs that Prolong the QT Interval and/or Induce Torsades de Pointes Ventricular Arrhythmia’.
• The top three medicines that may cause QTc prolongation should be listed.

Outcome

The article entitled ‘Cardiac vigilance recommended for methadone’ was amended and published on the Medsafe web site in November 2005. It was also published in the December 2005 edition of Prescriber Update.

Discussion

The Committee noted the above.

2.1.3 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk

September 2005 minute item 3.1

Reference

1. Sudbo J. et al. Non-steroidal anti-inflammatory drugs and the risk of oral cancer: a nested case-control study. Lancet. 2005; 366:1359-66

Issue

The Committee recommended that Medsafe continue to monitor the literature and liaise with international regulators regarding the potential for non-specific NSAIDs to increase the risk of cardiovascular adverse events. Medsafe should report back to the MARC on this issue, should new information become available.

The Committee recommended that Medsafe and the MARC should review the Australian evaluation of the non-specific NSAIDs when it became available.

Outcome

In October 2005, the Lancet published the results of a Norwegian nested case-control study investigating the effect of NSAID use on the development of oral cancer in heavy smokers. The study determined that NSAID use was protective against the development of oral cancer in heavy smokers. However, analysis of the secondary endpoint of cardiovascular death found that patients taking NSAIDs had double the risk of dying from cardiovascular disease than those not taking NSAIDs. The study was subject to significant bias and confounding, the majority of which was not identified and therefore could not be controlled for. For example, it was possible that the patients receiving NSAIDs were being treated for the pain of severe peripheral or cardiovascular disease and hence were at greater risk of cardiovascular death independent of NSAID use (i.e. confounding by indication). In addition, as the study only included heavy smokers, the results had limited generalisability. Therefore, this study did not add significantly to the body of literature regarding the risk of cardiovascular disease with non-specific NSAIDs that had already been reviewed by the MARC.

Medsafe agreed to continue to monitor the literature on this issue and report back to the Committee once the TGA evaluation of NSAID cardiovascular safety data was available.

Discussion

The Committee noted the above, and the reference provided for minute item 3.1.6 (Hudson et al, 2005) regarding the use of COX-2 inhibitors and NSAIDs in congestive heart failure. Members commented that the issue of whether the non-specific NSAIDs were associated with a similar risk of cardiovascular adverse events to the COX-2 inhibitors had not yet been resolved. Therefore, the MARC recommended that this issue should be placed on the active monitoring list (see minute item 3.1 for an explanation of active monitoring).

Recommendation

The Committee recommended that non-specific NSAIDs and cardiovascular adverse effects, including congestive heart failure, should be placed on the active monitoring list.

Medsafe comment

On 4 February 2006, subsequent to the MARC meeting, the Lancet published a full retraction of the article by Sudbo et al, which was reviewed by the MARC for this issue. The retraction occurred in response to confirmation from Prof Anders Ekbom, who chaired the investigating commission appointed by the University of Oslo, that the paper contained fabricated data. The Committee agreed that the Sudbo et al study had not added significantly to the body of evidence regarding the risk of cardiovascular events associated with the use of non-specific NSAIDs. Therefore, it is Medsafe's view that the Committee's recommendation to actively monitor this issue does not need to be rescinded.

2.1.4 Bisphosphonates and Osteonecrosis of the Jaw (ONJ)

September 2005 minute item 3.2

Issue

The Committee recommended that a Prescriber Update article be written to inform prescribers of the potential for ONJ to occur with bisphosphonate therapy and to reiterate management advice.

The Committee recommended that the Pamisol data sheet should be updated in line with the Aredia and Zometa data sheets. Novartis and Mayne Pharma should highlight osteonecrosis of the jaw as a heading in the ‘Warnings and Precautions’ sections of their data sheets.

The Committee recommended that Medsafe should continue to monitor the literature on this issue particularly with respect to the occurrence of ONJ with the oral bisphosphonates.

The Committee recommended that the NZPhvC should monitor reports of ONJ with bisphosphonates and report back to Medsafe and the MARC in six months, or earlier if warranted.

Outcome

Medsafe was drafting a Prescriber Update article on this issue.

Medsafe contacted Mayne Pharma and Novartis in November 2005 to inform them of the MARC’s recommendations for changes to the Pamisol and the Aredia/Zometa data sheets. A response had not yet been received from either sponsor.

Medsafe and NZPhvC agreed to prepare an updated report on bisphosphonates and ONJ for the September 2006 MARC meeting, or earlier if warranted.

Discussion

The Committee noted the above outcomes. Members noted that the risks of ONJ with bisphosphonates were not yet fully understood, particularly with respect to the oral agents. Therefore, they considered that it would be of value for this issue to be on the active monitoring list, with the first annual review due in September 2006 (see minute item 3.1 for an explanation of active monitoring).

Recommendation

The Committee recommended that bisphosphonates and osteonecrosis of the jaw should be placed on the active monitoring list, with the first annual review due in September 2006.

2.1.5 Review of Adverse Reactions of Current Concern

September 2005 minute item 3.3

Issue

The Committee recommended that Medsafe should investigate options for an Adverse Reactions of Current Concern/Drugs of Current Interest scheme for use in the JTA, including the use of a visual symbol.

The Committee recommended that the NZPhvC should investigate options for having adverse reactions of interest displayed during Grand Rounds.

Outcome

The recommendation regarding a scheme for use in the JTA was passed on to the JTA project team developing proposals for pharmacovigilance in the new Agency for consideration.

The NZPhvC intended to trial a mechanism with selected hospitals by which identified cases could be displayed at Grand Rounds. This process would require the hospitals’ Grand Round Convenors taking responsibility for ensuring the slides with the adverse drug reactions of interest were on display as the audience assembled.

Discussion

The Committee commented that it would be of value to formalise the processes around review of Adverse Reactions of Current Concern (ARCC). It was noted that NZPhvC provided a report to the MARC at every meeting on ARCC, as part of the Quarterly Report, and any spontaneous reports received by CARM on ARCC issues were brought to the MARC. Suggestions for improving the processes were to have the information regarding ARCC appear as a separate standing agenda item for each MARC meeting with relevant literature, case reports and international regulatory action discussed, and gathered together in section 4 of the meeting dossier. It would also be of value for spontaneous reports to CARM presented to the MARC on ARCC issues to be highlighted with a symbol. The Committee agreed that Medsafe and NZPhvC should discuss this issue further, and work to develop formalised review processes.

Recommendations

The Committee recommended that Medsafe and NZPhvC should discuss how best to formalise processes around the review of Adverse Reactions of Current Concern.

2.1.6 Review of Watching Briefs

September 2005 minute item 3.4

Issue

The Committee recommended that the following process should be followed for the assessment of watching briefs:

1. The issue should be clearly identified at the time of the recommendation.
2. Medsafe and NZPhvC should actively monitor emerging data and bring the issue back to the MARC as necessary.
3. Medsafe/NZPhvC should undertake an annual review of the issue on the anniversary of the recommendation, including a literature search, presentation of CARM data and assessment of national and international regulatory actions.
4. Following the annual review a decision as to whether to maintain the watching brief should be made.

The Committee recommended that Medsafe and NZPhvC should analyse the existing list of watching briefs and bring the results back to the MARC.

The Committee recommended that NZPhvC should reassess the criteria for recommending a watching brief to the Committee.

Outcome

See minute item 3.1.

2.1.7 Paroxetine and Use in Pregnancy

September 2005 minute item 3.5

Issue

The Committee recommended that a watching brief should be held for all SSRIs in pregnancy.

The Committee recommended that the data sheets for all paroxetine products should be updated as per the proposed data sheet for Aropax.

Outcome

Medsafe informed GlaxoSmithKline (GSK) that Medsafe and the MARC had accepted their proposed changes to the Aropax data sheet regarding the risk of congenital abnormalities when administered in the first trimester of pregnancy. The data sheet for Aropax had not yet been updated at the time of this meeting.

Medsafe also contacted AFT Pharmaceuticals to request that the data sheet for their generic brand, Paroxetine, be updated in line with the changes to the Aropax data sheet. The changes were made to the Paroxetine data sheet in October 2005.

Discussion

The Committee noted that, contrary to the minutes of the September 2005 MARC meeting, paroxetine had not been contraindicated for use in pregnancy in Australia, but instead was classified as pregnancy category C (medicines that have caused or are suspected of causing harmful effects to the foetus). Following the release of the preliminary data by GSK in September 2005, the Australian TGA strengthened the warnings on product information to advise against use during pregnancy.

The Committee was informed that on 9 December 2005, the FDA announced that, based on new data, paroxetine’s pregnancy category was being changed from C to D (indicative of positive evidence of human foetal risk) and further revisions of the labels for paroxetine products in the US were being made by the sponsor.

The FDA’s decision was based on the preliminary results of two recent unpublished epidemiological studies. The first study was an updated analysis from the GlaxoSmithKline (GSK) sponsored, retrospective, US epidemiological study of major congenital malformations following maternal exposure to antidepressants in the first trimester. The initial results of this study were provided to the MARC for their consideration at the September 2005 MARC meeting. The study population had been extended, now comprising 5,956 infants born to 5,791 women dispensed antidepressants during the first trimester. The updated analysis showed a trend towards an increased risk for cardiovascular malformations for paroxetine compared to other antidepressants (OR 1.54; 95% confidence interval 0.81-2.92).

The second study was a new study of delivery outcome following maternal use of SSRI antidepressants in early pregnancy, conducted utilising the Swedish national registry data. Previous published studies utilising these registry data, and provided to the MARC at the September 2005 meeting, found no evidence for an increased overall risk of major malformations with maternal exposure to SSRI medications, including paroxetine (Hallberg 2005, Ericson 1999). In this latest study, no increase in the overall rate of congenital malformations was observed in infants exposed to paroxetine (4.9%), compared with the general population rate (4.8%) (adjusted OR: 1.03; 95% confidence interval 0.75-1.41). There was, however, an increased risk for cardiac defects in infants exposed to paroxetine (OR 1.78, 95% confidence interval 1.12-2.75), which was contributed mainly by an increased risk of ventricular septal defects and atrial septal defects (OR 1.92; 95% confidence interval 1.12-3.10).

Medsafe informed the Committee that GSK had agreed to further update the NZ data sheet for Aropax to reflect the most recent data, and that Medsafe was in the process of reviewing these changes.

The Committee noted the above and agreed that the paroxetine data sheets should be updated to reflect the most recent available data.

2.1.8 Chlorpromazine and Neuroleptic Malignant Syndrome (CARM case 64723)

September 2005 minute item 4.1.1.2

Issue

The Committee recommended that NZPhvC should seek the opinion of intensive care specialists with regards to the off-label use of chlorpromazine to treat serotonin syndrome and subsequently bring this issue back to the MARC.

Outcome

NZPhvC sought the opinion of two specialists; an intensive care specialist responded that he was not aware of chlorpromazine being a suggested treatment option for serotonin syndrome, and he was not aware that it was being used off-label in this situation. He commented that there might be difficulties in using chlorpromazine for the treatment of serotonin syndrome, as clinically it could be difficult to distinguish between serotonin syndrome and neuroleptic malignant syndrome. A clinical pharmacologist responded similarly, and also gave the opinion that elevated serotonin levels were likely to increase dopamine antagonism and therefore increase the risk of neuroleptic malignant syndrome with chlorpromazine.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.9 Atorvastatin and Aggressive Reaction (CARM case 67166)

September 2005 minute item 4.1.5.1

Issue

The Committee recommended that NZPhvC should explore the option of writing a Prescriber Update article on the psychiatric adverse effects of the statins.

Outcome

See minute item 4.2.1 for a review of lipid-lowering agents and psychiatric adverse reactions. An article was to be drafted by NZPhvC, for publication internationally and subsequently in Prescriber Update.

2.1.10 Other CARM Case Reports

September 2005 minute items 4.1.9

Issue

The Committee recommended that CARM should bring the full details of case report 67081, tranexamic acid and transient ischaemic attack (TIA), to the MARC at the next meeting.

Outcome

See minute item 4.1.4.1 for the full details of this case report.

2.1.11 Analysis of IMMP Events Reported for Sibutramine

September 2005 minute item 4.2.1

Issue

The Committee recommended that Medsafe should obtain and review the US product information for sibutramine.

Outcome

Medsafe reviewed the US data sheet for sibutramine as recommended. After consultation with IMMP, Medsafe requested that Abbott include dyspepsia/gastritis and bruising/ ecchymosis as adverse effects in the sibutramine data sheet. As the completion of analyses for the entire IMMP sibutramine cohort were expected in early 2006, it was agreed that Medsafe would not request further changes to the sibutramine data sheet until the results were available.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.1.12 Sibutramine and Bruising

September 2005 minute item 4.2.2

Issue

The Committee recommended that IMMP should bring the full details of the cases of bruising with sibutramine to the MARC.

Outcome

IMMP confirmed that the case details presented in the report to the MARC meeting reflected the full extent of information available. No additional clinical information was available.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2 Report on Actions Arising from Previous Meetings of the MARC

2.2.1 MARC Membership – Vacant Positions

September 2005 minute item 2.1.1; June 2005 minute item 1.1.1.

Issue

In September 2005, the Committee recommended that Prof. Skegg should liaise with the preferred candidate for MARC membership.

Outcome

Medsafe was currently clarifying the process to be undertaken for appointing Committee members under the new Minister of Health.

Discussion

Medsafe informed the Committee that the Minister of Health had agreed to continue the practice whereby the Minister made appointments to Ministerial advisory committees without referral to the Cabinet Appointments and Honours Committee. The process for appointing new or alternative members to the MARC would require Medsafe to provide the Minister with several nominees for each vacant position. As the establishment of the Australia New Zealand Therapeutic Products Authority (ANZTPA) was to be delayed (see minute item 9.2), Medsafe explained that it would be seeking nominees for the vacant MARC positions in the near future. The Committee asked Medsafe to develop a list of interested candidates for the next MARC meeting.

2.2.2 COX-2 Inhibitors and Cardiovascular Safety

September 2005 minute item 2.2.1; June 2005 minute item 2.1.1; March 2005 minute items 3.1.8.1,2,4,5 and 6.

Issue

In March 2005, the Committee recommended that the data sheets and consumer medicine information (CMIs) for celecoxib, etoricoxib, lumiracoxib, parecoxib and meloxicam should be updated (see the minutes of the 121^st MARC meeting for details).

In March 2005, the Committee recommended that the sponsors of all COX-2 inhibitors should be asked to supply Medsafe with further data on the gastrointestinal effects and cardiovascular risks of their products, as well as any adverse events that came to their attention, as a condition of continuing Ministerial consent for distribution.

Outcome

The data sheets for celecoxib, etoricoxib, lumiracoxib, parecoxib and meloxicam had been updated to include all the required cardiovascular safety information, and had been published on Medsafe’s web site. The consumer medicine information (CMIs) for Arcoxia (etoricoxib), Mobic (meloxicam) and Prexige (lumiracoxib) had been similarly updated and published on the Medsafe web site. A reminder had been sent to the remaining sponsor.

All COX-2 inhibitor sponsors agreed to supply further safety data to Medsafe on a 6-monthly basis. Additionally, the sponsor of etoricoxib supplied assurance that they would provide data on the safety of etoricoxib use in patients with controlled hypertension, as such data became available.

Medsafe informed the COX-2 inhibitor sponsors that, once the data sheets were published on Medsafe’s web site, Medsafe was agreeable to resumption of professional advertising of the medicines.

A paragraph giving prescribers an update on COX-2 inhibitors was published in the December 2005 edition of Prescriber Update.

Discussion

Medsafe informed the Committee that the outstanding CMIs for Celebrex (celecoxib) and Dynastat (parecoxib) had been updated and published on Medsafe’s web site shortly before this meeting.

The Committee noted that professional advertising of some COX-2 inhibitors had been resumed.

The Committee noted the above outcomes and agreed that no further regulatory action was required at that time.

2.2.3 Valdecoxib and Serious Cutaneous Adverse Reactions (SCARs)

September 2005 minute item 2.1.4; June 2005 minute item 3.3

Issue

In June 2005, the Committee recommended that the data sheet for valdecoxib should be updated to address its cardiovascular risks, as per the recommendations made at the 121^st MARC meeting in March 2005.

In June 2005, the Committee recommended that Medsafe should accept Pfizer’s proposed data sheet changes for valdecoxib, in order to manage the risk of serious cutaneous adverse reactions, including:

• Limit the indicated use of valdecoxib in OA and RA to patients who have failed to respond to or could not tolerate non-selective NSAIDs and other selective COX-2 inhibitors.
• Remove the indication for valdecoxib in primary dysmenorrhoea.
• Mandate weekly visits for the first four weeks of each course of valdecoxib therapy.
• Amend the data sheet and patient/physician education materials to stress the importance of immediate discontinuation of valdecoxib and notification to the treating physician at the first evidence of dermal and/or mucosal signs or symptoms, especially during the first month of therapy.

Outcome

A response had not yet been received from the sponsor of Bextra (valdecoxib; Pfizer), regarding the required data sheet changes. Bextra was not marketed in NZ at the time of this meeting. Medsafe contacted Pfizer again requesting an update on the status of this product.

Discussion

Medsafe informed the Committee that Pfizer had recently responded agreeing to include all of the required cardiovascular and skin safety warnings in the data sheet for Bextra (valdecoxib). These changes had not yet been made. Bextra was not marketed in NZ at the time of this meeting.

The Committee noted that an article on severe cutaneous adverse reactions, which included information on valdecoxib, was published in the December 2005 edition of Prescriber Update.

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.4 Methotrexate, Leflunomide and Respiratory Adverse Effects (CARM cases 63532 and 64391)

September 2005 minute item 2.1.13; June 2005 minute items 4.2.11.2 and 4.2.11.3.

Issue

In June 2005, the Committee recommended that a brief Prescriber Update article should be written by NZPhvC to update prescribers on the respiratory adverse effects of leflunomide.

In September 2005, the Committee recommended that NZPhvC should write to the Thoracic Society asking them to remind members of the respiratory adverse effects of leflunomide.

Outcome

A paragraph reminding prescribers to watch for respiratory symptoms with leflunomide, with or without methotrexate, was published in the December 2005 issue of Prescriber Update. This would be followed by a more detailed Prescriber Update article in 2006.

The NZPhvC wrote to the Thoracic Society of Australia and New Zealand as requested.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.5 Colchicine Dosage

September 2005 minute item 2.1.14; June 2005 minute item 4.3.2

Reference

1. Medsafe Pharmacovigilance Team. Colchicine: Lower Doses for Greater Safety. Prescriber Update. To be published December 2005.

Issue

In June 2005, the Committee recommended that Medsafe should ask the sponsor of colchicine to review the dosage advice in the current data sheet.

In September 2005, the Committee recommended that Medsafe should explore the option of publishing a Prescriber Update article on colchicine, referencing the NZ Rheumatology Association (NZRA) Consensus Statement (altered to reflect the change to a 0.5mg tablet), once the 0.5mg product was marketed in NZ.

Outcome

Both Anspec (Colgout) and Abbott (Colchicine) made the requested changes to the data sheets. In September 2005, Colgout (0.5mg colchicine) gained provisional consent to market in NZ. It was listed as fully subsidised on the Pharmaceutical Schedule from 1 November 2005. There was to be a 6-month transition period where both strengths of colchicine tablet were listed and fully subsidised. Abbott intended to discontinue the Colchicine brand in NZ once existing stocks were exhausted.

A Prescriber Update article was written to inform prescribers about the new strength tablet and about the updated prescribing information. In order to provide timely advice to coincide with the availability of the 0.5mg colchicine tablet, the article was peer-reviewed by the MARC Chair and representatives of the NZ Rheumatology Association before being published on Medsafe’s web site in November 2005, and in the December 2005 edition of Prescriber Update.

In November 2005, the NZRA altered the Consensus Statement on their web site to reflect the change to a 0.5mg strength tablet.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.6 Salamol Inhaler – Device Failure Issues

September 2005 minute item 2.1.15; June 2005 minute item 4.3.3

Reference

1. Medsafe Summary Report (final draft). Salamol Inhalers: New Zealand Brand Switching Complaints Investigation. 12 December 2005. Emailed to MARC members on 14 December 2005.

Issue

In June 2005, the Committee recommended that Medsafe should assess the results of the further tests of Salamol inhalers and report back to the MARC at the next meeting.

In September 2005, the Committee recommended that Medsafe should explore options with relevant stakeholders in order to improve the management of future brand-switch issues arising from brand changes to Sole Subsidised Supply medicines.

Outcome

The final draft of the Medsafe report on the Salamol inhaler was emailed to members on 14 December 2005.

On 16 September 2005, representatives of PHARMAC, Medsafe and NZPhvC met to discuss options for improving the management of future brand-switch issues arising from brand changes to Sole Subsidised Supply medicines. The parties explored ways to ensure good communication and looked at mechanisms to ensure that this communication would happen.

A paragraph giving prescribers an update on Salamol inhalers was published in the December 2005 edition of Prescriber Update.

Discussion

The Committee noted that the final draft of the Medsafe report on Salamol inhalers had concluded that, following investigation and testing, Medsafe was satisfied that Salamol met the international requirements and guidelines for quality, safety and efficacy required for a medicine registered and distributed in New Zealand. The report included the results of the tests undertaken by the TGA, which had been awaited by the MARC. The report also concluded that:

• there appeared to be a lack of patient awareness regarding the cleaning requirements of Salamol inhalers, although Salamol (and Ventolin) inhalers carried statements to clean weekly.
• although brand switching information and cleaning information was available on the launch of Salamol in New Zealand, the amount and level of distribution of information appeared to have been insufficient at launch in order to adequately inform patients and health professionals about the importance of cleaning.
• the amount and distribution of patient information, particularly on cleaning of the device, had since been improved.

Medsafe explained that the market share for Salamol continued to grow. NZPhvC informed the Committee that occasional reports to CARM were still being received for Salamol.

The Committee noted that a meeting had taken place between Medsafe, PHARMAC and NZPhvC regarding options for improving the management of future brand-switch issues arising from brand changes to Sole Subsidised Supply medicines. Medsafe explained that the aim was ensure that prescribers and patients received consistent information from PHARMAC and Medsafe at the time of future brand-switches.

The Committee considered that no further regulatory action was required at that time.

2.2.7 Dextropropoxyphene/Paracetamol Combination Products and the Risk of Overdose

September 2005 minute item 2.1.2; June 2005 minute item 3.1

References

1. Extract from the minutes of the Medicines Adverse Reactions Committee meeting held on 9 June 2005.
2. Extract from the minutes of the Medicines Adverse Reactions Committee meeting held on 15 September 2005.
3. Usage data
   • PHARMAC prescription data – graph of number of scripts written monthly for Capadex and Paradex, from June 2004 to August 2005.
   • Sales data for Capadex 100’s and 500’s sold by Pharmacy Retailing (NZ) Ltd trading as Healthcare Logistics for the last 12 months by month.
   • Martinus D. Capadex sales: September 2005. Email 4 October 2005.
   • Martinus D. Capadex sales: October 2005. Email 15 November 2005.
   • Lazarus H. Paradex usage data: November 2003 to August 2005. 19 October 2005.
   • Lazarus H. Paradex usage for September and October 2005. Email 10 November 2005.
4. The Royal NZ College of General Practitioners. Capadex and Paradex. 11 October 2005.
5. NZ Pain Society. 17 October 2005.
   • Naesh O. Regarding Medsafe inquiry on paracetamol/ dextropropoxyphene. 7 October 2005.
6. Australian and NZ College of Anaesthetists. Dextropropoxyphene/ paracetamol combination products. 19 October 2005.
7. NZ Palliative Medicine Pharmaceuticals Group. Safety of Dextropropoxyphene/Paracetamol Combination Products (Capadex and Paradex). 18 October 2005.
8. Hospice NZ. Safety of Dextropropoxyphene/Paracetamol Combination Products (Capadex and Paradex). 14 October 2005.

Background

Dextropropoxyphene is a synthetic opioid analgesic structurally related to methadone. At the time of this meeting dextropropoxyphene/paracetamol combination products were indicated for use in New Zealand for the treatment of mild to moderate pain.

The MARC conducted a review of the risk:benefit profile of dextropropoxyphene/paracetamol combination products in June 2005. This followed the UK Medicines and Healthcare Products Regulatory Authority’s (MHRA’s) announcement in January 2005 that it would be withdrawing all dextropropoxyphene/paracetamol combination products over the subsequent 6-12 month period.

The MHRA’s decision was based on an unfavourable risk:benefit profile determined by poorly established evidence of efficacy, particularly in the treatment of acute pain, and clear evidence of serious toxicity in both intentional and unintentional overdose. The MHRA noted that, unlike with other opioid overdoses, dextropropoxyphene/paracetamol overdoses are particularly hazardous because death can occur too rapidly for medical rescue to be possible (within 15-30 minutes).

The MHRA sought public consultation on the efficacy and safety of these medicines prior to making the decision to withdraw the medicines from the UK. Submissions from practising clinicians including rheumatologists, general practitioners (GPs) and palliative care or pain specialists were supportive of the continued availability of these products. Submissions from evidence based prescribing advisors including the Royal College of GPs were supportive of withdrawal.

The MHRA concluded that the submissions did not provide any evidence of superior efficacy of dextropropoxyphene/paracetamol combination products compared to full strength paracetamol alone, and concluded that patient preference was likely to be due to the adjuvant central nervous system effects of dextropropoxyphene. Although some submissions suggested prescriber education was an important strategy for reducing prescribing, the MHRA asserted that past experience indicated that this strategy was only likely to be partially successful and therefore was unlikely to have a significant effect on reducing the number of dextropropoxyphene/paracetamol overdoses. It was noted that the Committee on Safety of Medicines (CSM) first drew prescribers’ attention to the toxicity of dextropropoxyphene in 1985.

The MHRA concluded that, based on the pharmacokinetics of dextropropoxyphene, its acute use could not be supported. However, as therapeutic levels were unlikely to be reached for several days this might explain its perceived efficacy (although there was no epidemiological evidence for this) in the treatment of chronic pain.

New Zealand experience

The New Zealand Poisons Centre performed an analysis of all opioid-related poisonings reported in New Zealand in 2001 and 2002. Dextropropoxyphene was assessed to be the primary cause of eight overdose deaths and was implicated in another eight overdose deaths. During that time period, dextropropoxyphene/paracetamol combination products accounted for almost 50% of all opioid prescriptions in New Zealand.

The NZ Ministry of Health had not previously issued any advice to prescribers regarding the toxicity of dextropropoxyphene-containing products in overdose.

Issue

In June 2005, the Committee recommended that the data sheets for Paradex, Capadex and Apo-Paradex should be updated to remove inconsistencies between them and to state the dosages of active ingredients.

In June 2005, the Committee recommended that Medsafe should obtain usage data for dextropropoxyphene/paracetamol combination products.

In June 2005, the Committee recommended that Medsafe should investigate options for restricting the period for which dextropropoxyphene/paracetamol combination products can be dispensed to thirty days.

In June 2005, the Committee recommended that Medsafe should undertake a period of consultation with stakeholders and then report back to the MARC.

Outcome

Data sheets

The sponsors of Paradex (Healthcare Manufacturing Group (HMG)), Capadex (Pharmacy Retailing NZ Ltd, trading as Healthcare Logistics) and Apo-Paradex (Apotex NZ Ltd) updated the data sheets as requested by Medsafe. As Apo-Paradex was not currently marketed in NZ the sponsor also requested that the data sheet be removed from Medsafe’s website.

The requested data sheet changes were related to the following issues:

• Stating clearly the dosages of active ingredients.
• Reducing the maximum daily dose so that a safe dose of paracetamol is administered.
• Contraindicating the concurrent use of alcohol and other paracetamol-containing products.
• Removing inconsistencies in the ‘Warnings and Precautions’ and ‘Overdosage; Treatment of paracetamol overdosage’ sections of the data sheets.

The package labels for dextropropoxyphene/paracetamol combination products were required to contain the following warning: "Do not drink alcohol while being treated with this medicine".

Usage data

PHARMAC data showed that, from June 2004 to August 2005, approximately 15,500-19,000 scripts per month were written for Paradex, and approximately 600-800 scripts per month were written for Capadex. The number of scripts written for both medicines remained reasonably stable over that time period. The sponsors of Capadex and Paradex also provided monthly sales data as requested. Neither Capadex nor Paradex was fully funded by PHARMAC over that time period.

Options for restricting dispensing period

At the September 2005 MARC meeting, Medsafe advised the Committee that currently there was no mechanism by which the quantities of dextropropoxyphene/paracetamol combination products dispensed could be restricted to 30 days supply for all patients prescribed these medicines. The Committee expressed their disappointment at this outcome.

Stakeholder consultation

In August 2005 Medsafe contacted stakeholders seeking submissions on the use of dextropropoxyphene/paracetamol combination products. The following responses were received:

1. The Royal NZ College of General Practitioners
   Summary:
   • There is a definite therapeutic need for these products.
   • The patients who gain the most benefit are the elderly and those requiring relief from mild to moderate pain.
   • College members noted the evidence that these products may be no more efficacious than paracetamol alone, however their experience is that patients do find them better.
   • These products are nearly always well tolerated, and are a practical and useful intermediary step in the analgesic ladder.
   • The College supports these medicines remaining available on the NZ market, but with restrictions.
2. The NZ Pain Society
   Summary:
   • Given four hourly this provides doses of paracetamol and dextropropoxyphene at the upper limits of the recommended level.
   • There is evidence of accumulation over three days.
   • Dextropropoxyphene has other effects such as NMDA receptor antagonism, which may count for its popularity in patients with an element of neuropathic pain.
   • These products are also of benefit for persistent pain of benign or malignant origin.
   • If these products are made unavailable, the pressure will be on prescribers to prescribe opioids. Particularly worrying would be if short-acting opioids were prescribed more frequently.
   • In NZ there are no real alternatives to these products at present.
   • Limiting the recommended dose is a possible strategy.
3. The Australian and NZ College of Anaesthetists
   Summary:
   • The arguments for discontinuation seem compelling.
   • The College supports removing the products, as there are better and safer alternatives.
4. NZ Palliative Care Pharmaceuticals Group
   Summary:
   • There are conflicting opinions in the palliative care community on the role these drugs in analgesia.
   • There are not enough data in the chronic/palliative populations to show whether they are more efficacious or not than paracetamol alone.
   • Steady-state concentration is 5-7 times more than after single dose, thus providing a theoretical reason why these products are likely to be more effective than paracetamol in chronic dosing.
   • These products clearly have a major role in NZ based on the number of prescriptions.
   • There is a therapeutic need for these products in NZ.
   • The patients gaining most benefit are those with mild-moderate cancer pain.
   • The Group supports these medicines remaining on the NZ market for palliative care populations.
   • The Group supports the removal of the acute indications and highlighting warnings in the data sheet.
   • There is no evidence that restricting prescribing or dispensing would make any impact on mortality.
5. Hospice NZ
   Summary:
   • Despite the evidence, many practitioners have experience of palliative care patients who prefer these products to paracetamol. A possible reason is that studies have been on patients from the acute setting, not palliative care.
   • Pharmaceutical treatments available to palliative care patients are few. Proposals to further limit the options are concerning.
   • Although there is some support for limiting the period dispensed to 30 days, this would still allow sufficient for overdose.
   • Consideration needs to be given to removing the acute indications and limiting funding to Special Authority.

The dextropropoxyphene/paracetamol combination product sponsors did not make further submissions regarding the safety of their products.

Discussion

The Committee noted the submissions from stakeholders detailed above. They considered that the submissions presented a strong case that there were patient populations for which the benefits of these products might outweigh the risks. Members noted that there were limited alternative analgesic products currently funded in NZ.

The Committee noted that the stakeholder submissions appeared to support removing the acute indications and limiting funding to Special Authority, and members considered that these actions would be appropriate.

The MARC reiterated their previous opinion that the presently available evidence suggested that dextropropoxyphene/paracetamol combination products had an unfavourable risk:benefit profile for routine use as an analgesic in acute pain. They noted that there was still no published evidence of increased efficacy compared to full-strength paracetamol alone. However, as stakeholders had provided opinions that there might be a clinical need for these products for some patients, the Committee considered that they should be allowed to remain on the NZ market, with restrictions. These restrictions should include limiting the indications to the treatment of chronic pain of moderate severity for patients in whom treatment with therapeutic doses from alternative therapeutic groups, including combination products, had been used and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient. Additionally, the Committee recommended that Medsafe should request that PHARMAC consider restricting the funding of dextropropoxyphene/paracetamol combination products to Special Authority.

The Committee considered that it would be of value for a Prescriber Update article to be published in order to:

• inform prescribers of these new restrictions, once they were in place
• advise that these products should not be used except in appropriate clinical situations
• increase awareness of the risk of inadvertent overdose with concomitant alcohol.

Members noted that, because NZPhvC does not collect overdose data in NZ, it would not be possible to monitor this issue under the hierarchy developed in minute item 3.1. Therefore, the Committee considered that this issue should be reviewed in two years, including analysis of an industry census of patient use, overdose data from the NZ Poisons Centre, prescription data and usage data.

Recommendations

The Committee recommended that the indications in the dextropropoxyphene/paracetamol combination product data sheets should be updated to limit use to the treatment of chronic pain of moderate severity for patients in whom treatment with therapeutic doses from alternative therapeutic groups, including combination products, had been used and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient.

The Committee recommended that Medsafe should request that PHARMAC consider restricting the funding of dextropropoxyphene/paracetamol combination products to Special Authority.

The Committee recommended that Medsafe should explore the option of publishing an article in Prescriber Update recommending that dextropropoxyphene/paracetamol combination products should not be used except in appropriate clinical situations, and to increase awareness of the risk of inadvertent overdose with concomitant alcohol use.

The Committee recommended that the issue of dextropropoxyphene/paracetamol combination products and the risk of overdose should be reviewed in two years, including analysis of an industry census of patient use, overdose data from the NZ Poisons Centre, prescription data and usage data.

2.2.8 Phenytoin, Fluorouracil and Ataxia, Dizziness, Drug Level Increased (CARM case 62606)

September 2005 minute item 2.1.10; June 2005 minute item 4.1.10.1

Issue

In June 2005, the Committee recommended that the data sheet for 5-fluorouracil should be updated to address the interaction with phenytoin.

Outcome

Medsafe wrote to Pfizer and Mayne Pharma to request that the potential interaction between phenytoin and 5-fluorouracil (5FU) or capecitabine be included in the phenytoin and 5FU data sheets. A response was awaited from the sponsors.

Discussion

The Committee noted the above and agreed that Medsafe should report back to the MARC once responses had been received from the sponsors.

2.2.9 Analysis of IMMP Events Reported for Risperidone

September 2005 minute item 2.1.16; June 2005 minute item 4.4.2

Issue

In June 2005, the Committee recommended that the data sheet for risperidone should be updated to include reference to the adverse reactions of seizures, epistaxis and dysphagia.

Outcome

In July 2005, Medsafe requested that Janssen-Cilag update the risperidone data sheet to include information on the risk of epistaxis and dysphagia and the occurrence of seizures in patients without a prior history of epilepsy.

Janssen-Cilag responded to Medsafe’s request in October 2005. They agreed to add information on dysphagia to the ‘Precautions’ section of the risperidone data sheet, and to add epistaxis to the ‘Adverse Effects’ section of the data sheet. However Janssen-Cilag did not agree to add the information in italics (below) to the precaution about seizures:

Other Precautions

Classical neuroleptics are known to lower the seizure threshold. Caution is recommended when treating patients with epilepsy. However, it should be noted that seizures have also occurred in patients without a history of epilepsy.

The sponsor argued that, as seizures were listed in the ‘Adverse Events – Less Common’ section of the data sheet, there was no need for an additional warning statement.

Discussion

The Committee noted the above and agreed that the current data sheet was acceptable with respect to the information provided on seizure risk, and that no further regulatory action was required at that time.

2.2.10 Pergolide and Cardiac Valvulopathy.

September 2005 minute item 2.2.4; June 2005 minute item 2.2.6; December 2004 minute item 3.3

Reference

1. PHARMAC media release. 2 new treatments funded for Parkinson’s disease. 27 October 2005.

Issue

In December 2004, the Committee recommended that a Prescriber Update article should be written on pergolide and cardiac valvulopathy. The article should also advise that pergolide should not be used off-label for the treatment of restless legs syndrome.

In June 2005, the Committee recommended that Medsafe should write to PHARMAC again with a brief reminder of the previous request [to consider the safety data on pergolide when making funding decisions] and asking to be kept informed of any review of funding for a non-ergot derivative dopamine agonist.

Outcome

At their September 2005 meeting, the MARC was informed that Medsafe considered that a Prescriber Update article on pergolide and cardiac valvulopathy was no longer required as there had not been any new information published since the ‘Dear Health Professional’ letter was distributed in January 2005. The only outstanding issue was regarding the off-label use of pergolide in restless legs syndrome. The MARC noted that the literature supported the efficacy of pergolide in the treatment of restless legs syndrome and hence off-label use for this indication was likely. Medsafe agreed to write to the sponsor asking them to send a ‘Dear Healthcare Professional’ letter advising prescribers that pergolide should not be used in this situation and reiterating MARC’s advice on fibrotic reactions. Therefore, Medsafe proposed that the Prescriber Update article be rescinded.

On 27 October 2005, PHARMAC announced that the non-ergoline dopamine agonist ropinirole (Requip) and the catechol-O-methyl transferase (COMT) inhibitor entacapone (Comtan) would be fully subsidised from 1 November 2005 for the treatment of Parkinson’s disease.

Discussion

Also see minute items 2.1.1 and 3.1.15.

The Committee agreed that the pergolide sponsor should be asked to distribute a ‘Dear Healthcare Professional’ letter reiterating MARC’s advice that pergolide should only be used for its approved indications, and specifically advising prescribers that pergolide should not be used off-label to treat restless legs syndrome. The Committee agreed this action would resolve this issue and the Prescriber Update article should therefore be rescinded.

Recommendation

The Committee recommended that Medsafe should ask the pergolide sponsor to send a ‘Dear Healthcare Professional’ letter reiterating MARC’s advice that pergolide should only be used for its approved indications, and specifically advising prescribers that pergolide should not be used off-label to treat restless legs syndrome.

The Committee recommended that the scheduled Prescriber Update article on pergolide and cardiac valvulopathy should be rescinded.

2.2.11 Domperidone and the Risk of QT Prolongation.

September 2005 minute item 2.2.5; June 2005 minute item 2.2.7; December 2004 minute item 3.4

Issue

In June 2005, the Committee recommended that Medsafe should write to Janssen-Cilag again, to request that the New Zealand data sheet for domperidone be updated to adequately inform prescribers of the risk of QT prolongation and/or sudden cardiac death with oral domperidone.

Outcome

In July 2005, Medsafe requested that the following information be included in the domperidone data sheet:
"^aCases of QTc prolongation, arrhythmia and sudden death have occurred with domperidone use. Although most reported cases have occurred in patients receiving the intravenous form of domperidone,^b an association with oral domperidone cannot be ruled out. Therefore, domperidone should be used with caution in patients with other risk factors for QTc prolongation including hypokalaemia, severe hypomagnesaemia, structural heart disease, the concomitant administration of other QTc prolonging medicines or an underlying genetic predisposition."

In September 2005, the domperidone data sheet was updated to include the above information. In addition, Janssen added "very rare" to position (a) above, and "or with other risk factors" to position (b).

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.12 Low Molecular Weight Heparins (LMWHs) in Renal Impairment.

September 2005 minute item 2.2.6; June 2005 minute item 2.2.11; September 2004 minute item 2.1.6; June 2004 minute item 2.1.4; March 2004 minute item 2.1.8; December 2003 minute item 4.1.1.5

References

1. Letter. Quality Safe Use of Medicines. 6 October 2005.
2. Hulot J. et al. Dosing strategy in patients with renal failure receiving enoxaparin for the treatment of non-ST-segment elevation acute coronary syndrome. Clin Pharm and Therapeutics. 2005; 77(6): 542-52

Issue

In June 2005, the Committee recommended that Medsafe should contact the DHBNZ Safe Use of Medicines Group to enquire on the progress of the development of a protocol for the safe use of LMWHs in patients with severe renal impairment.

Outcome

The DHBNZ Safe Use of Medicines Group responded to Medsafe in October 2005. Medsafe was informed that an alert was currently being developed to advise prescribers on the required enoxaparin dosage adjustment for patients with renal impairment (creatinine clearance <50mL/min). In view of a lack of data for other LMWHs this advice would not be extrapolated to the other LMWHs available in New Zealand. After consultation throughout New Zealand the Safe Use of Medicines Group determined that there was only limited ability to perform anti-Xa monitoring in New Zealand and therefore monitoring could not be recommended routinely.

Discussion

The Committee noted the above and agreed that Medsafe should bring the DHBNZ Safe Use of Medicines Group protocol to the MARC once it was finalised.

2.2.13 Sodium Valproate and Pancreatitis (CARM case 63175)

June 2005 minute item 4.1.4.1

Issue

In June 2005, the Committee recommended that a brief Prescriber Update article should be written by NZPhvC to highlight medicines that commonly cause pancreatitis.

Outcome

An article on drug-induced pancreatitis was published in the December 2005 edition of Prescriber Update.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.14 Mometasone and Rosacea (CARM case 62554)

June 2005 minute item 4.1.7.1

Issue

In June 2005, the Committee recommended that NZPhvC should write a brief Prescriber Update article to remind prescribers about the risks associated with the use of corticosteroids on the face.

Outcome

An article on the risks of using topical corticosteroids on the face was published in the December 2005 edition of Prescriber Update.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.15 Miconazole, Warfarin Interaction and Haematuria, Prothrombin Increased (CARM case 63753)

June 2005 minute item 4.2.3.2

Issue

In June 2005, the Committee recommended that there should be a short article published in Prescriber Update reminding prescribers of the interaction between miconazole and warfarin.

Outcome

A paragraph on miconazole oral gel interaction with warfarin was published in the December 2005 edition of Prescriber Update.

Discussion

The Committee noted the above and agreed that no further regulatory action was required at that time.

2.2.16 Pimecrolimus Application Site Reactions

March 2004 minute item 2.1.14

Issue

In March 2004, the Committee recommended that prescribers be informed about the possibility of severe application site reactions with pimecrolimus by way of an article in Prescriber Update.

Outcome

After reviewing the available evidence, CARM and Medsafe concluded that the Prescriber Update article on severe application site reactions with pimecrolimus was no longer required. MARC recommended this article after reviewing a cluster of reports of severe reactions received by CARM in late 2003. The Prescriber Update article was intended to highlight the potential for the occurrence of these reactions, particularly in children. Many of these were company reports. Since the MARC recommendation only four further reports of application site reactions had been received by CARM; the only severe reaction involved an adult.

It was CARM’s opinion that, in the absence of ongoing empirical evidence for the problem, a Prescriber Update article was no longer warranted. Medsafe supported this position. However, in the event of more cases being identified, the need for such an article could be reconsidered.

Discussion

The Committee noted the above and agreed that the Prescriber Update article was no longer warranted.

Recommendation

The Committee recommended that the scheduled Prescriber Update article on pimecrolimus application site reactions should be rescinded.

3. pharmacovigilance issues

3.1 Review of Watching Briefs

Background

'Watching brief' is one of the tools available to MARC for managing pharmacovigilance issues. Since March 2001, the MARC had recommended on 35 occasions that a watching brief be held for an adverse reaction to a medicine. It was generally understood that the adverse reaction data and international literature would be actively monitored for that particular pharmacovigilance issue, and a report would be provided to the MARC as new information became available. However, prior to September 2005 there were no formal procedures in place for the assessment or review of watching briefs by Medsafe, NZPhvC or MARC.

At the September 2005 MARC meeting the Committee considered that it would be valuable to have formal processes in place for the review of medicines under watching brief. After discussion, the following process was decided upon.

• The issue should be clearly identified at the time of the recommendation.
• Medsafe and NZPhvC should actively monitor emerging data and bring the issue back to the MARC as necessary.
• Medsafe should undertake an annual review of the issue on the anniversary of the recommendation, including a literature search, presentation of CARM data and assessment of national and international regulatory actions.
• Following the annual review a decision as to whether to maintain the watching brief should be made by MARC.

The Committee discussed how best to assess the existing list of watching briefs. They concluded that Medsafe and NZPhvC should, following investigation of each issue, remove any items from the list for which regulatory action had been concluded. The results of this process should be reported back to the MARC. Subsequently, starting with those watching briefs recommended in 2001, Medsafe should review each item (including a literature search, CARM data and an update on regulatory action taken) and present the results to the MARC. Additionally, NZPhvC should reassess the criteria for recommending a watching brief to the Committee.

In October and November 2005, Medsafe and NZPhvC reviewed the existing list of watching briefs as recommended by the MARC. It was jointly agreed that some medicines could be removed from the list, without further review by the Committee:

1. Those medicines monitored in the Adverse Reactions of Current Concern (ARCC) programme (i.e. leflunomide – all adverse reactions; complementary medicines – all adverse reactions; SSRIs - severe agitation, severe restlessness/akathisia, and/or increased suicidality). Medsafe and NZPhvC actively monitor the ARCC medicines. NZPhvC provides a report to the MARC at every meeting on ARCC, as part of the Quarterly Report, and any spontaneous reports for ARCC medicines received by CARM are brought to the MARC.
   
   Implementation of this policy led to the following watching briefs being removed:
   • Kava and liver toxicity (watching brief instigated 11/9/2002)
   • Fish oil and hepatic enzymes increased (22/6/2004)
   • Glucosamine and hyperkalaemia (16/12/2004)
   • Joint-X and hyperkalaemia (16/12/2004)
   • Leflunomide and cardiovascular disorders in susceptible people (26/6/2003)
   • Leflunomide and hypoglycaemia (22/6/2004)
   • Leflunomide and toxicity in renal impairment (22/6/2004)
   • Leflunomide and headache/cystitis/haematuria (22/9/2004)
   • Leflunomide and pneumonitis (16/12/2004)
2. Those medicines monitored in the Intensive Medicines Monitoring Programme (IMMP), because IMMP actively monitors reactions to the medicines in the programme and brings an analysis of any data of interest to the MARC.
   
   Implementation of this policy led to the following watching briefs being removed:
   • Clozapine and hyperglycaemia/fever (watching brief instigated 11/9/2002)
   • Risperidone and oedema (26/6/2003)
   • Risperidone and stroke (10/3/2004)
   • Risperidone and sudden death (22/6/2004)
   • Risperidone and cerebrovascular adverse reactions (22/9/2004)
   • Risperidone and mortality in elderly especially with dementia (9/6/2005)
   • Sibutramine and prolonged QT (22/6/2004)
   Note that the COX-2 inhibitors were no longer being actively monitored by IMMP, therefore they remained on the watching brief list for review.
3. It was found that there were three issues where duplicate recommendations had been made. Therefore, the following items were combined:
   • SSRIs and haemorrhage (20/6/2002) combined with SSRIs and gastrointestinal bleeding (26/6/2003).
   • Rosiglitazone and lipid abnormalities (22/6/2004) combined with rosiglitazone and decreased HDLc and hypertriglyceridaemia (9/6/2005).
   • OTC medicines and errors (16/12/2004) combined with Panafen and brand name confusion (16/12/2004).

Two watching briefs were recommended in 2005, therefore, would come up for review on their anniversary of recommendation:

• COX-2 inhibitors and hypertension, cardiac failure, renal dysfunction and allergic reactions (15/3/2005)
• SSRIs and teratogenicity (15/9/2005).

Medsafe and the NZPhvC reviewed each remaining watching brief issue (with the exception of tramadol and hepatic reactions which would be reviewed for the March 2006 meeting) and provided a report for the MARC. The reports generally included information on:

• when the watching brief was recommended
• when the product was approved in NZ
• CARM case reports before and after the watching brief was recommended
• previous MARC reviews and regulatory outcomes
• international regulatory action
• data sheets
• recent literature
• conclusions and recommendations.

Please see minute items 3.1.1 to 3.1.16 for discussion and recommendations on these reports.

NZPhvC reassessed the criteria for recommending a watching brief to the Committee. The NZPhvC proposed that 'watching brief' should be considered as an internal (NZPhvC/Medsafe/ MARC) process with the purpose of monitoring pharmacovigilance issues for which there was emerging evidence of safety concerns such as increased numbers of case reports or published literature.

Medsafe proposed that a three-level hierarchy be used in the future for recommending the ongoing monitoring of an issue. For example, ‘watching brief’, ‘actively monitor’ the issue and ‘standing agenda item’. Medsafe proposed to include a table in each MARC dossier summarising the issues being monitored under the above three categories.

Medsafe asked that the Committee discuss each watching brief report and consider the following:

1. Should the issue continue to be monitored by Medsafe and NZPhvC?
2. If so, which of the above three levels of monitoring would be most appropriate?

Discussion

The Committee supported the decisions made by Medsafe and NZPhvC to remove some items from the original list of watching briefs, as detailed above.

The Committee agreed that, in the future, watching briefs should be monitored under three categories. Following discussion, it was decided that these should be as follows:

1. Watching brief
   Low-level monitoring. Medsafe and NZPhvC should monitor the issue and provide a brief annual report to the MARC including information on case reports in the CARM and WHO databases. If concerns emerged prior to the annual review the issue should be brought back to the MARC at the next meeting. The watching brief should expire in one year if there were no further concerns, or if deemed necessary the issue could be promoted to active monitoring or standing agenda item at that time.
2. Active monitoring (with formalised review)
   Intermediate-level monitoring. Medsafe and NZPhvC should actively monitor the issue and provide an annual report to the MARC. In addition to information on case reports in the CARM and WHO databases, there should be a review of the recently published literature and international regulatory actions. If concerns emerged prior to the annual review the issue should be brought back to the MARC at the next meeting. Active monitoring status could be demoted to watching brief status after one year if the issue had been resolved, or if deemed necessary the issue could be promoted to standing agenda item status.
3. Standing agenda item
   High-level monitoring. Medsafe and NZPhvC should actively monitor the issue, and all new data should be reported to the MARC at every meeting, including information on case reports in the CARM and WHO databases, recently published literature and international regulatory action. Adverse Reactions of Current Concern should be included in this category (see minute item 2.1.5). A decision should be made at each meeting of whether to maintain standing agenda item status, or to demote the issue to active monitoring or watching brief status.

The Committee agreed that the definitions of these monitoring levels should be revisited at the next meeting once some experience in using them had been obtained. The Committee considered that it would be of value for a summary table to be provided in each meeting dossier, listing the issues being monitored under the above three categories. It would also be useful for the summary to provide links to related case reports or other information in the dossier.

Recommendation

The Committee recommended that, in the future, pharmacovigilance issues of concern should be monitored and reviewed under one of three categories: watching brief, active monitoring or standing agenda item.

3.1.1 Bupropion and Cardiovascular Adverse Effects

Issue

This watching brief was recommended in March 2001. Bupropion was first approved in NZ in May 2000 as a prescription medicine.

There were 48 cardiovascular reports to CARM prior to initiation of the watching brief, and nine reports subsequently.

The MARC reviewed this issue on five occasions between December 2000 and March 2002. In September 2001, MARC recommended that bupropion should only be used as second line therapy for smoking cessation, following a trial of nicotine replacement, and a Prescriber Update article was published in October 2001.

NZPhvC commented that, anecdotally, the use of bupropion had declined following MARC action and the Prescriber Update article. Reports to CARM also declined at the same time. Occasional reports of diverse adverse reactions were received by CARM. Literature reports were predominantly of overdose and one report confirmed the previous observation of a cardiac association. No further issues had been identified with bupropion. NZPhvC recommended that this issue should be removed from the watching brief list.

Discussion

The Committee noted that, anecdotally, the market sales of bupropion were now very low, and that other products and services were now available to assist smoking cessation. They commented that it was difficult to know what the usage of bupropion was like in other countries. They agreed that the issue had been adequately explored and resolved, and that therefore it should be removed from the watching brief list.

Recommendations

The Committee recommended that bupropion and cardiovascular adverse effects should be removed from the watching brief list.

3.1.2 Selective Serotonin Reuptake Inhibitors (SSRIs) and Haemorrhage

References

1. Paton C. Ferrier IN. SSRIs and gastrointestinal bleeding. BMJ. 331(7516): 529-30, 2005 Sep 10.
2. Meijer WEE, Heerdink ER, Nolen WA, Herings RMC, Leufkens HGM, Egberts ACG. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med 2004; 164: 2367-70.

Issue

This watching brief was recommended in June 2002. SSRIs were approved in NZ as prescription medicines in: fluoxetine 1988; sertraline 1992; venlafaxine (an SNRI) 1993; paroxetine 1997; citalopram 1997; reboxetine 2000; escitalopram 2002.

Prior to initiation of the watching brief there were two reports to CARM of haemorrhage for paroxetine, two for fluoxetine and one for citalopram. Subsequently there were no reports for paroxetine or fluoxetine and one report for citalopram.

The MARC reviewed this issue on five occasions between December 2001 and June 2004. Recommendations included writing a Prescriber Update article (which was later rescinded due to equivocal evidence at that time), and updating the data sheets. Some of the data sheets were updated as requested, however, two sponsors provided reports that disagreed with the MARC’s recommendation. Consequently, the SSRI data sheets remained inconsistent regarding the information included on the risk of haemorrhage.

For this meeting the Committee was provided with two recently published papers further supporting an association between SSRIs and abnormal bleeding.

Medsafe recommended to the MARC that the SSRI sponsors should be asked again to update their data sheets, in order to provide consistent information regarding the risk of abnormal bleeding associated with their use, and that this issue should be removed from the watching brief list.

Discussion

The Committee commented that it was clear that there was an increased risk of bleeding with SSRIs, and the concomitant use of SSRIs and NSAIDs/aspirin was of particular concern. They agreed that the data sheets for the SSRIs should be updated to address the risk of abnormal bleeding and to make the warnings consistent, and that a paragraph should be published in Prescriber Update. Members agreed that this issue should be removed from the watching brief list, following resolution of the above regulatory actions.

Recommendations

The Committee recommended that the SSRI data sheets should be updated to adequately address the risk of abnormal bleeding and to be consistent with one another.

The Committee recommended that Medsafe should write a paragraph for publication in Prescriber Update informing prescribers of the risk of abnormal bleeding with SSRIs, and emphasising the risks of co-prescribing NSAIDs/aspirin.

The Committee recommended that SSRIs and haemorrhage should be removed from the watching brief list, following resolution of the above regulatory actions.

3.1.3 COX-2 Inhibitors/Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Impaired Fracture Healing

Issue

This watching brief was recommended in March 2003. COX-2 inhibitors were first approved in NZ in: Mobic (meloxicam) July 1998; Celebrex (celecoxib) September 1999; Vioxx (rofecoxib) January 2000 (voluntarily withdrawn October 2004); Arcoxia (etoricoxib) October 2002; Dynastat (parecoxib) February 2003; Bextra (valdecoxib) May 2003 (voluntarily withdrawn April 2005); Prexige (lumiracoxib) November 2004.

There had been no reports to CARM of impaired fracture healing associated with COX-2 inhibitor or NSAID use.

The MARC reviewed this issue on three occasions between September 2002 and March 2003. Expert opinion was sought, and the MARC concluded that, while there was consistent in vitro evidence that NSAIDs could inhibit fracture healing, there was very little evidence to suggest a clinical effect. They did not recommend regulatory action other than the watching brief.

Medsafe informed the Committee that, after reviewing the literature subsequent to 2003, it was still unclear whether the use of NSAIDs or COX-2 inhibitors was associated with a clinically significant impairment of fracture healing. As there had not been any recent studies published providing evidence of this association and there had not been any reports to CARM, Medsafe recommended that this issue should be removed from the watching brief list.

Discussion

The Committee noted that animal and in vitro studies continued to show an increased risk of impaired fracture healing with NSAIDs and COX-2 inhibitors, but that there was no further evidence of a clinical effect. They noted that the references cited were all review articles and that no new clinical studies had been published since the MARC last considered the issue. They considered that it would be of value to seek an updated opinion from experts in this area. As this issue was not yet resolved, members agreed that it should continue to be monitored on the watching brief list.

Recommendations

The Committee recommended that Medsafe should write again to experts in this area, seeking an updated opinion on the clinical risk of impaired fracture healing with COX-2 inhibitors/NSAIDs.

The Committee recommended that COX-2 inhibitors/NSAIDs and impaired fracture healing should continue to be monitored on the watching brief list.

3.1.4 Rosiglitazone and Pancreatitis

Issue

This watching brief was recommended in June 2003. Rosiglitazone was first approved in NZ in June 2000 as a prescription medicine.

There have been no reports to CARM of pancreatitis with rosiglitazone.

The MARC reviewed this issue in June 2003 following publication of a signal found in the WHO database (Vigibase). As this was a serious suspected adverse reaction and rosiglitazone had recently become available in New Zealand it was decided by MARC that a watching brief should be commenced.

No further evidence was found in the literature of this association. As at June 2005, five reports of pancreatitis with rosiglitazone had been added to Vigibase, giving a total of 69 reports.

NZPhvC recommended that this issue should be removed from the watching brief list, and that they should suggest to the Uppsala Monitoring Centre (UMC) that the data in Vigibase be re-analysed with a view to publication.

Discussion

The Committee noted that there were 69 reports in the WHO database of rosiglitazone and pancreatitis, with a positive Information Component (IC) value. They supported NZPhvC contacting the UMC.

The Committee recommended under minute item 3.1.7 that all serious or unexpected adverse reactions to rosiglitazone should be on the standing agenda item list.

Recommendations

The Committee recommended that the NZPhvC should contact the UMC suggesting that the data in Vigibase on rosiglitazone and pancreatitis be re-analysed with a view to publication if the signal was considered strong enough.

3.1.5 Selective Serotonin Reuptake Inhibitors (SSRIs) and Withdrawal Reactions

Issue

This watching brief was recommended in June 2003. SSRIs were approved in NZ as prescription medicines in: fluoxetine 1988; sertraline 1992; venlafaxine (an SNRI) 1993; paroxetine 1997; citalopram 1997; reboxetine 2000; escitalopram 2002.

Prior to initiation of the watching brief there were 18 reports to CARM of withdrawal reactions for paroxetine, three for fluoxetine and none for citalopram. Subsequently there were five reports for paroxetine, none for fluoxetine and two reports for citalopram.

The MARC reviewed this issue in 1997, at which time data sheet changes and a Prescriber Update article were recommended. Subsequently, it was reviewed on two occasions, in September 2002 and June 2003. The watching brief was recommended when this issue was brought to the MARC following recent media interest in the UK in June 2003. In March and October 2004, Medsafe issued ‘Dear Doctor’ letters giving updated information and advice about the use of antidepressant medicines, including the advice "Antidepressant medicines should not be stopped abruptly – doses should be tapered off gradually". These letters were also published in the November 2004 issue of Prescriber Update.

In December 2004 the UK MHRA Committee on Safety of Medicines (CSM) issued advice on the safe use of SSRIs in adults, including withdrawal reactions.

Medsafe concluded that withdrawal syndromes with SSRIs, particularly the short-acting products, were well described and were discussed in the product data sheets in NZ (with the exception of citalopram). Therefore, Medsafe recommended that this issue should be removed from the watching brief list.

Discussion

The Committee noted that the data sheet for Cipramil (citalopram) contained little information regarding the risks of withdrawal reactions. They considered that Medsafe should explore the evidence for withdrawal reactions with citalopram, including an interrogation of the CARM and WHO databases, and if there was adequate evidence ask the citalopram sponsors to update the data sheets. As this action would resolve this issue, the Committee considered it should be removed from the watching brief list.

Recommendations

The Committee recommended that Medsafe should review the evidence regarding the risks of withdrawal reactions with citalopram, and consider asking the product sponsors to update the data sheets.

The Committee recommended that SSRIs and withdrawal reactions should be removed from the watching brief list.

3.1.6 COX-2 Inhibitors and Cardiovascular Adverse Events

References

1. Hippisley-Cox J et al. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005;330:1366, doi:10.1136/bmj.330.7504.1366
2. Hudson M et al. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib or non-steroidal anti-inflammatory drugs: population based study. BMJ 2005;330:1370, doi:10.1136/bmj.330. 7504.1370
3. Kasliwal R et al. A Comparison of Reported Gastrointestinal and Thromboembolic Events Between Rofecoxib and Celecoxib Using Observational Data. Drug Safety 2005; 28 (9): 803-816
4. Aldington S et al. Systematic review and meta-analysis of the risk of major cardiovascular events with etoricoxib therapy. NZMJ 2005; Vol 118 No 1223 http://www.nzma.org.nz/journal/118-1223/1684/

Issue

This watching brief was recommended in September 2002. COX-2 inhibitors were first approved in NZ in: Mobic (meloxicam) July 1998; Celebrex (celecoxib) September 1999; Vioxx (rofecoxib) January 2000 (voluntarily withdrawn October 2004); Arcoxia (etoricoxib) October 2002; Dynastat (parecoxib) February 2003; Bextra (valdecoxib) May 2003 (voluntarily withdrawn April 2005); Prexige (lumiracoxib) November 2004.

Prior to initiation of the watching brief there were 248 cardiovascular adverse reaction reports to CARM for celecoxib, 157 for rofecoxib, 11 for etoricoxib and none for valdecoxib. Subsequently, there were 112 reports for celecoxib, 91 for rofecoxib, 42 for etoricoxib and 6 for valdecoxib.

The MARC reviewed this issue on 14 occasions between December 2000 and September 2005. Following the worldwide withdrawal of Vioxx by Merck in October 2004, Medsafe requested that all COX-2 inhibitor sponsors provide a copy of all cardiovascular safety data held. Recommendations were made at the December 2004 meeting based on preliminary data, and advice was disseminated to prescribers. Further advice was disseminated following an extraordinary meeting between Medsafe and the MARC Chair in February 2005.

In March 2005, the MARC conducted a full review of the cardiovascular safety of the COX-2 inhibitors and concluded that the risk:benefit ratio remained favourable for a select group of patients only. The main recommendations made were for extensive changes to the data sheets and consumer medicine information, for the sponsors to provide ongoing usage and safety data and for the watching brief to be maintained. These recommendations were communicated to prescribers in April 2005, and the data sheets were updated (other than valdecoxib), under section 36 of the Medicines Act 1981, by November 2005. (Also see minute item 2.2.2)

In April 2005, at Medsafe’s request, Pfizer agreed to voluntarily withdraw Bextra (valdecoxib) from the NZ market (in line with similar withdrawals in the US, Canada and the EU), pending review of the risk of severe cutaneous adverse reactions (SCARs) by Medsafe and the MARC, which occurred at the June 2005 MARC meeting. The MARC considered that Bextra’s consent to market could be maintained as long as the data sheet was updated to include the information on cardiovascular risk required for all COX-2 inhibitors and also the changes recommended by Pfizer in order to manage the risk of SCARs. (Also see minute item 2.2.3)

Cardiovascular events with COX-2 inhibitors were monitored as Adverse Reactions of Current Concern from February 2002 to April 2004. COX-2 inhibitors were monitored under the Intensive Medicines Monitoring Programme (IMMP) from December 2000 to July 2005.

Four recently published papers were provided to the Committee for this meeting, the findings of which were consistent with previous literature reviewed by the MARC.

Medsafe recommended to the MARC that the watching brief recommended in March 2005 regarding COX-2 inhibitors and skin reactions, hypertension, cardiac failure, renal dysfunction and allergic reactions should be combined with the watching brief on COX-2 inhibitors and cardiovascular reactions. Medsafe recommended that this issue should remain on the watching brief list until Medsafe had received and evaluated the first six months safety data that would be provided by the COX-2 inhibitor product sponsors.

Discussion

The Committee noted the extensive history of regulatory action taken on this issue. They agreed with Medsafe’s recommendations as detailed above and considered that this issue should be placed on the active monitoring list. Also see minute items 2.2.2 and 2.2.3.

Recommendations

The Committee recommended that the watching brief recommended in March 2005 regarding COX-2 inhibitors and skin reactions, hypertension, cardiac failure, renal dysfunction and allergic reactions should be combined with the watching brief on COX-2 inhibitors and cardiovascular reactions. This combined issue should be placed on the active monitoring list until Medsafe had received and evaluated the first six months safety data that would be provided by the COX-2 inhibitor product sponsors.

3.1.7 Rosiglitazone and Cardiac Failure

References

1. GlaxoSmithKline. Avandia: Preliminary results from Analysis of Cardiovascular Events in Clinical Trials. 14 October 2005.

Issue

This watching brief was recommended in March 2004. Rosiglitazone was first approved in NZ in June 2000 as a prescription medicine.

Prior to initiation of the watching brief there was one report of cardiac failure with rosiglitazone in the CARM database. Subsequently, there have been two reports of cardiac failure and two reports of oedema.

MARC reviewed this issue in March 2004 following a spontaneous case report to CARM. It was noted that the data sheet for Avandia stated that thiazolidinediones could cause fluid retention, which could exacerbate congestive heart failure. It also stated that patients at risk of heart failure (particularly those on insulin) should be monitored for signs and symptoms of heart failure. The purpose of the watching brief arising from this report was to monitor reports to CARM to assess if there was evidence that prescribers may be unaware of the prescribing advice regarding rosiglitazone and heart failure.

Following evaluation of the post-watching brief case reports, including two for pioglitazone, there was no evidence that the thiazolidinediones were being prescribed to people with uncontrolled heart failure. Patients with ischaemic heart disease, valvular heart disease or hypertension were at risk of developing cardiac failure and it seemed that in some cases the thiazolidinedione might have exacerbated this process. Thiazolidinediones were appropriately withdrawn when fluid retention occurred. NZPhvC recommended that the watching brief be discontinued.

Discussion

The Committee noted the recent CARM case reports. They noted the paper provided was a summary of preliminary results of a GlaxoSmithKline (GSK) study on rosiglitazone, alone or in combination with other hypoglycaemics, and cardiovascular adverse events.

Members noted that major cardiovascular risk factors had been controlled for. The results showed no significant increase in risk of congestive heart failure, although further investigation was possibly required for the combinations of rosiglitazone/insulin, rosiglitazone/sulfonylurea/metformin and rosiglitazone/ sulfonylurea. Members noted that rosiglitazone was not currently funded, but that pioglitazone was fully funded under Special Authority, with the warning in the Pharmaceutical Schedule that it should never be used in patients with heart failure. They noted that the data sheet for Avandia (rosiglitazone) contained warnings regarding fluid retention in the ‘Precautions’, ‘Adverse Reactions’ and ‘Dosage and Administration’ sections, but that use in cardiac failure was not contraindicated.

The Committee considered that it would be valuable to remind prescribers of the cardiovascular effects of rosiglitazone through Prescriber Update. They agreed that NZPhvC should review the published literature and case reports to determine whether the article could be expanded to include pioglitazone and/or other adverse reactions to thiazolidinediones. They also agreed that all serious or unexpected adverse reactions to rosiglitazone should be on the standing agenda item list, for review at the next MARC meeting; that Medsafe should ask GSK for updated data and subsequently consider updating the Avandia data sheet; and that NZPhvC should consider presenting this issue at Grand Rounds.

Recommendations

The Committee recommended that all serious or unexpected adverse reactions to rosiglitazone should be on the standing agenda item list.

The Committee recommended that Medsafe should request updated data from GlaxoSmithKline and subsequently consider updating the rosiglitazone data sheet regarding the cardiovascular risks.

The Committee recommended that Medsafe should explore the option of publishing a short paragraph in Prescriber Update on the cardiovascular adverse effects of rosiglitazone, and to remind prescribers about the contraindications and relative contraindications for use. Following further investigation of the literature and case reports by NZPhvC, this article could be extended to also include pioglitazone, and/or other adverse reactions to thiazolidinediones if warranted.

The Committee recommended that NZPhvC should explore the option of presenting adverse reactions to rosiglitazone at Grand Rounds.

3.1.8 Topiramate and Serious Psychiatric Reactions

Issue

This watching brief was recommended in March 2004. Topiramate was first approved in NZ in June 1998 as a prescription medicine.

Prior to initiation of the watching brief there were four reports of serious psychiatric adverse events with topiramate in the CARM database. Subsequently, there have been no reports.

The MARC reviewed this issue in March 2004 following a spontaneous case report to CARM of a patient being treated off-label for migraine who developed depression and suicidal ideation. At the time of this case report topiramate was not indicated for the treatment of migraine. The Committee was concerned with the potential risks associated with the off-label use of this medicine and recommended the watching brief. In April 2004, Medsafe approved an additional indication "in adults for the prophylaxis of migraine headache". An updated data sheet was published on Medsafe’s web site in May 2004. In July 2004, the data sheet for Topamax was updated with information on depression and suicidality.

Medsafe recommended that, as the Committee had been primarily concerned with the off-label use of topiramate in migraine, this issue should be removed from the watching brief list.

Discussion

The Committee noted that topiramate was fully funded under Special Authority for use in epilepsy, but not in migraine. Anecdotal reports were that usage of topiramate was low and targeted to appropriate patients.

The Committee agreed that the issue had been adequately explored and resolved, and that it should be removed from the watching brief list.

Recommendations

The Committee recommended that topiramate and serious psychiatric reactions should be removed from the watching brief list.

3.1.9 Rosiglitazone and Lipid Abnormalities

Reference

1. Savage RL and Kiuru A. Thiazolidinediones and lowered HDL cholesterol (letter). Diabetes Care 2005; 28(9): 2329-2330.

Issue

This watching brief was recommended in June 2004. Rosiglitazone was first approved in NZ in June 2000 as a prescription medicine.

Prior to initiation of the watching brief there was one report of high density lipoprotein cholesterol (HDLc) decreased and one report of triglycerides increased with rosiglitazone in the CARM database. Subsequently, there has been one report of HDLc decreased and no reports of triglycerides increased.

The MARC recommended the watching brief in June 2004, following a spontaneous report to CARM of lipid abnormalities in a patient taking rosiglitazone. The issue was reviewed in June 2005 following another report to CARM, whereupon the Committee supported publication of NZPhvC’s paper in the WHO’s Signal publication, and recommended maintaining the watching brief. The paper concluded that voluntary adverse drug reaction reports and published case series indicated that rosiglitazone alone or in combination with a fibrate might decrease serum HDLc levels. The CARM case reports, international case reports and literature were also presented to ASCEPT NZ meeting in August 2005 and at the International Society of Pharmacovigilance (IsoP) meeting in October 2005.

NZPhvC recommended to the MARC that this issue should remain on the watching brief list.

Discussion

The Committee noted that they had considered this issue at the June 2005 meeting, and since that time there had been one more case report from Canada. They noted that hypercholesterolaemia had been observed with rosiglitazone in clinical trials, particularly in combination with fibrates, and that there had been post-marketing reports of decreased HDLc, with and without concomitant fibrate use. The literature reported these effects in combination, but not with rosiglitazone alone.

The Committee recommended under minute item 3.1.7 that all serious or unexpected adverse reactions to rosiglitazone should be on the standing agenda item list.

3.1.10 DTaP/IPV/Hep B/HiB Vaccine and Sudden Death

Issue

This watching brief was recommended in September 2004. Combined diphtheria-tetanus-acellular pertussis, enhanced inactivated polio, hepatitis B and haemophilus influenza type B (DtaP/IPV/ HepB/HiB) vaccine was first approved in NZ in 2000 as a prescription medicine.

Prior to initiation of the watching brief there were two reports of sudden death with DtaP/IPV/HepB/ HiB vaccine in the CARM database. Subsequently, there have been no further reports.

The MARC reviewed two case reports of sudden death following DTaP/IPV & HiB/HepB immunisation, in December 2003 and September 2004. In both cases the causality was deemed to be unclassifiable.

NZPhvC commented that the issue of sudden infant death syndrome (SIDS) in association with immunisation had been extensively reviewed over time in the literature, which consistently concluded no negative association and often a protective one. Inevitably, unexplained SIDS cases were likely to be observed in the context of widespread immunisation exposure when coverage rates were high. NZPhvC recommended that this issue should be removed from the watching brief list.

Discussion

The Committee noted the above. They considered that this issue had been adequately explored, and that it should be removed from the watching brief list.

Recommendations

The Committee recommended that Hib/Hep B, DTaP/IPV vaccine and sudden death should be removed from the watching brief list.

3.1.11 Cephazolin and Pancreatitis

Issue

This watching brief was recommended in December 2004. Cephazolin was first approved in NZ in 1974 as a prescription medicine.

Prior to initiation of the watching brief there was one report of pancreatitis with cephazolin in the CARM database. Subsequently, there have been no further reports.

The MARC considered this issue in December 2004 following a spontaneous report to CARM with a positive dechallenge. The Committee recommended a watching brief.

As no references to this association were found in the literature, and there had been no further reports, Medsafe recommended that this issue should be removed from the watching brief list.

Discussion

The Committee noted the above. They considered that this issue had been adequately explored, and that it should be removed from the watching brief list.

Recommendation

The Committee recommended that cephazolin and pancreatitis should be removed from the watching brief list.

3.1.12 MMR Vaccine and Arthritis

Issue

This watching brief was recommended in December 2004. MMR vaccine was first approved in NZ in 1990 as a prescription medicine.

Prior to initiation of the watching brief there were six reports of arthritis, 20 of arthralgia and two of arthropathy with MMR vaccine in the CARM database. Subsequently, there have been no further reports of arthritis or arthropathy, and two reports of arthralgia.

The MARC considered this issue in December 2004 following a spontaneous report to CARM of septic-type arthritis post-MMR immunisation. They recommended a watching brief.

NZPhvC commented that transient arthritis post-MMR immunisation was listed in the product data sheet for MMR-II as well as standard vaccinology texts. Some debate in the literature had focussed on chronic arthropathies post-MMR where immune-mediated mechanisms had been postulated as an initiating factor in cases of persisting arthropathy. Chronic post-MMR arthropathy was also addressed in the MMR-II data sheet. The case report that precipitated the watching brief was of a transient nature. NZPhvC recommended to the MARC that this issue should be removed from the watching brief list.

Discussion

The Committee noted the above. They considered that this issue had been adequately explored, and that it should be removed from the watching brief list.

Recommendation

The Committee recommended that MMR vaccine and arthritis should be removed from the watching brief list.

3.1.13 Domperidone and QT Prolongation

Issue

This watching brief was recommended in December 2004. Domperidone was first approved in NZ in 1982 as a prescription medicine, although was not marketed until 1986.

There had been no reports to CARM of QT prolongation, arrhythmia or sudden death associated with domperidone use, either prior or subsequent to the watching brief being recommended.

The MARC reviewed this issue on three occasions from December 2004 to June 2005. The initial review was precipitated by the publication of an FDA Health Advisory in June 2004 warning pregnant women against using domperidone to stimulate lactation because of reports of arrhythmia and sudden death with the intravenous formulation of the medicine. The MARC recommended that the domperidone data sheet should be updated to indicate that domperidone should be used cautiously in patients with other risk factors for QT prolongation and should not be prescribed concomitantly with CYP3A4 inhibitors such as erythromycin. Following extensive debate with the sponsor, the data sheet was updated in September 2005 to include information on the potential risk of QT prolongation. However, Medsafe agreed to await further data on CYP3A4 interactions before requiring further data sheet changes.

In June 2005, MARC recommended that the Medicines Classification Committee (MCC) should be informed that the MARC would not support the sponsor’s application for reclassification of oral domperidone to over-the-counter status until this safety issue had been satisfactorily resolved.

As regulatory action was now complete on this issue and there had not been any further literature reports or reports to CARM, Medsafe recommended to the MARC that domperidone and QT prolongation, arrhythmia and/or sudden death should be removed from the watching brief list.

Discussion

The Committee noted the history of regulatory action on this issue, and that the data sheets in NZ and Australia were now updated. They noted that the MCC had declined the application for the reclassification of domperidone to a restricted medicine in June 2005. They considered that this issue had been resolved, and that it should be removed from the watching brief list.

Also see minute item 2.2.11.

Recommendation

The Committee recommended that domperidone and QT prolongation should be removed from the watching brief list.

3.1.14 Over-the-Counter (OTC) Medication Errors

Issue

This watching brief was recommended in December 2004.

Prior to initiation of the watching brief there were two reports of medication errors with OTC medicines in the CARM database. Subsequently, there have been no further reports. In the first report the patient had been prescribed Brufen (ibuprofen) by her GP and had also purchased OTC Nurofen (ibuprofen). In the second report the patient inadvertently took ibuprofen rather than paracetamol for pain relief. The ibuprofen was branded as Panafen and the patient assumed it contained paracetamol.

The MARC reviewed the two cases above in December 2004 and recommended the watching brief. No further regulatory action had been taken on this issue.

Medsafe had been unable to locate any recent literature specifically addressing errors associated with the administration of OTC medicines.

As there had not been any further reports of OTC medication errors, Medsafe recommended to the MARC that this issue be removed from the watching brief list.

Discussion

The Committee noted the two cases described above. Medsafe explained that it was difficult to monitor the literature on this issue. Members noted that Panafen was an international brand name for ibuprofen and that it was difficult to assess the extent of this problem. The Committee agreed that the brand name Panafen could be confusing for patients, but that the MARC had no control over the name.

Medsafe explained that under the Australia New Zealand Therapeutic Products Authority (ANZTPA) there were plans to introduce rules around ‘umbrella branding’ of products, to reduce the ability for products containing new or different active ingredients to be included under an existing ‘umbrella brand’ name. The Committee was informed that the Authority would address this issue during the pre-market evaluation of products, and therefore the Committee recommended that it should be removed from the watching brief list.

Recommendation

The Committee recommended that over-the-counter (OTC) medication errors should be removed from the watching brief list.

3.1.15 Pergolide and Cardiac Valvulopathy

Issue

This watching brief was recommended in December 2004. Pergolide was first approved in NZ in October 2003 as a prescription medicine.

CARM had not received any reports of cardiac valvulopathy in association with pergolide use, either prior or subsequent to the watching brief being recommended.

The MARC reviewed this issue on three occasions between December 2004 and September 2005. In April 2003 the data sheet was updated and a ‘Dear Healthcare Professional’ letter was sent by the sponsor warning prescribers of case reports of cardiac valvulopathy related to pergolide use. The data sheet was further updated in July 2004 and February 2005 to include information on ‘Serious Inflammation and Fibrosis’ under ‘Precautions’. The sponsor had included the advice that baseline echocardiograms should be performed in patients currently taking pergolide and prior to the initiation of new patients on pergolide.

The MARC reviewed the available evidence in December 2004 and concluded that fibrotic reactions with pergolide were likely to represent a class effect for all ergot derivative dopamine agonists, but that it was not possible to determine the true incidence of valvulopathy with pergolide from currently available data. They recommended a Prescriber Update article, including the advice that pergolide should not be used off-label to treat restless legs syndrome. The sponsor distributed a ‘Dear Health Professional’ letter to New Zealand prescribers in January 2005 to inform them of the risks of fibrotic reactions, including valvulopathy, and advising that baseline echocardiograms should be obtained for all patients prior to initiating treatment with pergolide.

Medsafe commented to the MARC that there had still not been any prospective studies conducted since the watching brief was issued and therefore it was still not possible to determine the prevalence of fibrotic reactions associated with pergolide use. Recent published literature on this issue consisted of case reports and retrospective studies, which were subject to a number of methodological problems including the inability to exclude pre-existing valvular abnormalities. In view of the absence of any new information available from the literature, the absence of any reports to CARM of pergolide-associated valvulopathy and PHARMAC’s decision to fund ropinirole (a non-ergot dopamine agonist), Medsafe recommended that pergolide and cardiac valvulopathy be removed from the watching brief list.

Discussion

The Committee noted that recent papers in the literature had not improved knowledge of the prevalence of fibrotic reactions with pergolide. They noted that the data sheet for pergolide had been updated, and two ‘Dear Healthcare Professional’ letters had been sent out on this issue.

The Committee reiterated their opinion that baseline echocardiograms might be difficult to obtain for all patients prescribed pergolide, particularly in rural areas. However, it was agreed that resourcing issues should not be a reason for compromising patient safety, and hence the MARC would not advise against baseline echocardiograms. They considered that PHARMAC’s decision to fully fund the non-ergoline dopamine agonist ropinirole (Requip) and the catechol-O-methyl transferase (COMT) inhibitor entacapone (Comtan) from 1 November 2005 for the treatment of Parkinson’s disease would be likely to significantly decrease the usage of pergolide.

The Committee considered that, as it was likely that fibrotic reactions were a class effect for all ergot derivative dopamine receptor agonists, it would be of value to place agents other than pergolide on the active monitoring list.

Also see minute items 2.1.1 and 2.2.10.

Recommendations

The Committee recommended that pergolide and cardiac valvulopathy should be removed from the watching brief list.

The Committee recommended that all ergot derivative dopamine receptor agonists (other than pergolide) and fibrotic reactions should be placed on the active monitoring list.

3.1.16 Valproate and Foetal Abnormalities

Issue

This watching brief was recommended in December 2004. Valproate was first approved in NZ in 1975 as a prescription medicine.

Prior to initiation of the watching brief there were seven reports of foetal disorders with valproate in the CARM database. Subsequently, there have been no further reports.

The MARC recommended the watching brief in December 2004 following a spontaneous case report to CARM of a child born with probable foetal valproate syndrome.

There had been no regulatory action on this issue, and the current valproate data sheet contained extensive warnings regarding the risks of use in pregnancy

NZPhvC commented that a recent paper added evidence to valproate alone as an aetiological factor conferring risk in foetal abnormalities. As this reaction was well known and adequate warnings were contained in the data sheet, it was recommended that this issue be removed from the watching brief list.

Discussion

The Committee noted that foetal abnormalities with valproate were well documented in the data sheet and considered that prescribers should be aware of this issue. As this issue had been adequately explored they agreed that it should be removed from the watching brief list.

Recommendation

The Committee recommended that valproate and foetal abnormalities should be removed from the watching brief list.

4. matters arising from the new zealand pharmacovigilance centre

Note: In the comment associated with each report, the case has been given a causality designation using terms and definitions developed by the WHO. The precise definitions are available on the website of the WHO Collaborating Centre http://www.who-umc.org/. These designations (certain, probable, possible, unlikely, unclassified and unclassifiable) refer to the degree of certainty about the relationship between the medicine and the adverse event. The terms should not be understood literally. For example, "certain" means that the appropriate elements are present to match the international definition. It does not mean there is absolute certainty that the medicine caused the adverse event.

Explanations of the terms used by CARM and MARC can be accessed by hyperlink at each causality designation.

4.1 Centre for Adverse Reactions Monitoring (CARM) Case Reports

4.1.1 Deaths

4.1.1.1 Enoxaparin and haemorrhage, circulatory collapse, renal failure and abdominal pain [death] (66385)

Discussion

The Committee noted that they had discussed serious haemorrhage with enoxaparin on many occasions in the past, in relation to CARM reports (see minute item 2.2.12). Factors identified from CARM reports as being important in determining the severity of the haemorrhage were a lack of dose adjustment in renal impairment, older age and the presence of unstable coronary artery disease.

The Committee noted that a general physician commented to the Coroner that the use of enoxaparin in this case was appropriate, but that there were no published guidelines about the duration of treatment with low-molecular weight heparins (LMWHs) in acute coronary syndrome. The Coroner recommended that the District Health Board (DHB) should amend its guidelines to include a recommended duration of administration of enoxaparin for persons presenting with conditions similar to those in this case. This issue was addressed by the DHB, who concluded that renal function was one of the most important determinants when considering dose and duration of treatment, and that anti-Xa monitoring should be considered if treatment continued for more than one week. The DHBNZ Safe Use of Medicines Group had been informed of the findings of the Coroner and the DHB response for consideration in the development of a protocol on the use on LMWHs in renal impairment (see minute item 2.2.12).

The causal association with enoxaparin was deemed to be 'probable' for haemorrhage, circulatory collapse, renal failure and abdominal pain. The Committee agreed that no further regulatory action was required at that time.

4.1.1.2 Enoxaparin and cerebral haemorrhage [death] (68589)

Discussion

Also see minute items 2.2.12 and 4.1.1.1.

The Committee noted that CARM had requested the autopsy report, and further information about renal function and concomitant medicines, but replies had not yet been received.

The causal association with enoxaparin was deemed to be 'probable' for cerebral haemorrhage. The Committee agreed that no further regulatory action was required at that time.

4.1.1.3 Peg-interferon alfa-2A and suicide (68147)

Discussion

The Committee noted a tabled document 'Revised data sheet information for MARC report – Pegasys RBV'.

The Committee noted that ribavirin should also be considered a suspect medicine in this case, due to its co-administration with peg-interferon alfa-2A. However, the published and other evidence favoured interferon to be the most likely causative agent.

Members commented that this was a well-recognised adverse reaction, and that psychiatrists routinely assessed patients’ mental state prior to treatment with peg-interferon alfa-2A. They noted that the data sheets for these products contained abundant information on the risk of psychiatric adverse effects, and that the addition of ribavirin to peg-interferon alfa-2A therapy substantially increased the risk.

The causal association with peg-interferon alfa-2A and ribavirin was deemed to be 'unclassifiable' for suicide. The Committee agreed that no further regulatory action was required at that time.

4.1.1.4 Tiotropium and cardiac failure and coronary artery disorder [death] (67503)

Discussion

NZPhvC provided members with an assessment of the serious cardiovascular adverse reaction reports received for tiotropium compared to ipratropium (a short acting anticholinergic medicine), in the CARM and WHO databases. The WHO data indicated that ipratropium was associated with similar cardiovascular adverse effects to tiotropium. However, in both databases there was a higher rate of reporting of atrial fibrillation for tiotropium than for ipratropium. NZPhvC explained that most of the cardiovascular tiotropium reports received had been from the product sponsor, and causality had been difficult to assess.

The Committee noted that on 1 February 2005, tiotropium became fully funded for the treatment of severe chronic obstructive pulmonary disease (COPD) equal to or greater than grade 4 according to the Medical Research Council dyspnoea scale (stops for breath after walking about 100 meters or after a few minutes on the level). There were several restrictions, including that the patient's forced expired volume in one second (FEV1) had to be <0.4 of the predicted value and they must have trialled a dose of at least 40mcg ipratropium four times daily in addition to standard treatment.

The Committee noted that, as patients with COPD had a higher incidence of cardiac failure, it was not possible to determine causality in this instance. They commented that this patient had not been treated with any medicines to treat cardiovascular disorders.

The Committee considered that the causal association with tiotropium should be changed from 'unlikely' to 'possible' for coronary artery disorder. Also see minute item 4.1.1.5 for a further case report involving tiotropium.

The causal association with tiotropium was deemed to be 'unclassified' for cardiac failure, and 'possible' for coronary artery disorder. The Committee agreed that no further regulatory action was required at that time.

Recommendation

The Committee recommended that the causal association with tiotropium should be changed from 'unlikely' to 'possible' for coronary artery disorder in this case (67503).

4.1.1.5 Tiotropium and myocardial infarction and dyspnoea [death] (68258)

Discussion

Also see minute item 4.1.1.4.

The Committee noted that in this case an autopsy had not been performed, however the cause of death was suspected myocardial infarction.

The causal association with tiotropium was deemed to be 'unclassified' for myocardial infarction and dyspnoea. The Committee agreed that no further regulatory action was required at that time.

4.1.2 Alternative Medicines

4.1.2.1 Herbal preparation and mixed hepatitis and jaundice (68104)

Discussion

The Committee noted that all adverse reactions to complementary medicines are Adverse Reactions of Current Concern.

The Committee noted that this Korean herbal preparation contained eight herbal ingredients ground with honey and made into pills. The NZPhvC had investigated each of the stated ingredients and could find no obvious cause for this hepatic reaction. They considered that without analysis of the pills it was impossible to ensure that the preparation was not adulterated or substituted. The Committee agreed that it would be of value to ask for samples to be sent to Australia for analysis.

The causal association with the herbal preparation was deemed to be 'possible' for mixed hepatitis and jaundice.

Recommendation

The Committee recommended that NZPhvC should obtain a sample of the Korean herbal preparation and provide it to Medsafe for analysis.

4.1.3 Antibacterials

4.1.3.1 Nitrofurantoin and dyspnoea, cough and pulmonary infiltration (67409)

Discussion

The Committee noted that a Prescriber Update article was published in 2002 describing pulmonary reactions with nitrofurantoin. At that time there were nine reports of pulmonary fibrosis in the CARM database, and since publication there had been a further six reports, including this one and that described as minute item 4.1.3.2. The patients in all six reports had been taking nitrofurantoin for ten months to five years.

Of concern to the Committee was that, in this case, the cough and dyspnoea continued for one year before nitrofurantoin was discontinued. They considered that it would be of value to remind prescribers through a paragraph in Prescriber Update about the importance of monitoring for respiratory adverse effects of nitrofurantoin and informing patients of the warning symptoms.

The causal association with nitrofurantoin was deemed to be 'probable' for dyspnoea, cough and pulmonary infiltration.

Recommendation

The Committee recommended that Medsafe should consider publishing a paragraph in Prescriber Update reminding prescribers about the importance of monitoring for respiratory adverse effects of nitrofurantoin and informing patients of the warning symptoms.

4.1.3.2 Nitrofurantoin and cough, abnormal renal function and pulmonary infiltration (67410)

Discussion

See minute item 4.1.3.1 for discussion and recommendations on this issue.

The Committee queried whether the patient's renal impairment could have influenced the outcome in this case. They suggested that NZPhvC should investigate this issue and consider including the results in the Prescriber Update article recommended under minute item 4.1.3.1.

The causal association with nitrofurantoin was deemed to be 'probable' for cough and pulmonary infiltration, and 'possible' for renal function abnormal.

4.1.4 Antihaemorrhagics

4.1.4.1 Tranexamic acid and transient ischaemic attack, hypoaesthesia (67081)

Discussion

The Committee noted that the dose of tranexamic acid taken in this case was within the recommended range for the treatment of menorrhagia. NZPhvC explained to the Committee that the diagnosis of transient ischaemic attack (TIA) was suspected but not confirmed. However, as there was no term for hemianaesthesia in the CARM database, this case was recorded as a TIA. Members queried the duration of the suspected TIA, and NZPhvC agreed to investigate further.

The Committee noted that a Prescriber Update article was published in 2003 on thrombosis with tranexamic acid for menorrhagia. They noted that of 528 reports for tranexamic acid in the WHO database, 22 were for cerebral embolism, 9 for arterial thrombosis and 56 for deep vein thrombosis and/or pulmonary embolism.

The causal association with tranexamic acid was deemed to be 'probable' for transient ischaemic attack and hypoaesthesia.

Recommendation

The Committee recommended that NZPhvC should investigate the duration of the suspected transient ischaemic attack in this case, and subsequently bring this issue back to the MARC.

4.1.5 Anti-inflammatories

4.1.5.1 Ibuprofen and ulcerative stomatitis (67419)

Discussion

The NZPhvC explained that this reaction was brought to the MARC because serious reactions in children were not often reported to CARM, and there was a current debate on the relative risk:benefit profiles of paracetamol and ibuprofen when used in children.

The Committee noted that of 25,549 reports in the WHO database for ibuprofen there were 119 reports of ulcerative stomatitis, with a positive IC value. In the CARM database, of a total of 194 reports for ibuprofen six were of stomatitis, one of glossitis and one of ulcerative stomatitis.

Regarding uncertainty around the diagnosis in this case, members commented that it was unlikely to be geographic tongue, which is not painful, and was unlikely to be a fixed drug eruption, which usually occur within eight hours.

The causal association with ibuprofen was deemed to be 'possible' for ulcerative stomatitis. The Committee agreed that no further regulatory action was required at that time.

4.1.6 Antineoplastics

4.1.6.1 Temozolomide and agranulocytosis (67320)

Discussion

The NZPhvC explained to the Committee that this case was reported to CARM because the reporter, an oncology professor, wanted to record that this neutropenic response differed from the neutropenia that occurred commonly with this medicine, in that the onset was later and it was more severe and prolonged.

The causal association with temozolomide was deemed to be 'possible' for agranulocytosis. The Committee agreed that no further regulatory action was required at that time.

4.1.7 Cardiovascular Medicines

4.1.7.1 Ezetimibe and amnesia (67317)

Discussion

Also see minute item 4.2.1 for discussion on the psychiatric adverse effects of lipid-lowering agents. This case report was brought to the MARC because it was the first report of memory impairment with ezetimibe, although this is a well-known adverse effect of the statins. The Committee commented that the mechanism of action for lipid-lowering was different for statins, fibrates and ezetimibe.

The Committee noted that there were a total of 21 reports for ezetimibe in the CARM database, but no others of memory impairment. There was one report of irritability and aggression, and one of confusion. Of a total of 4,354 reports in the WHO database, there were 19 reports of amnesia with a negative IC value.

The causal association with ezetimibe was deemed to be 'certain' for amnesia. The Committee agreed that no further regulatory action was required at that time.

4.1.8 Contrast Media

4.1.8.1 Iopromide and parotitis (67765)

Discussion

The Committee noted that isolated reports in the literature indicated that 'iodide mumps' was an uncommon complication of contrast media containing iodide.

The causal association with iopromide was deemed to be 'probable' for parotitis. The Committee agreed that no further regulatory action was required at that time.

4.1.9 Drug Interactions

4.1.9.1 Warfarin/tramadol and purpura, decreased prothrombin (67421)

Discussion

The Committee noted that of a total of 94 reports in the CARM database for tramadol, there was one other of an interaction with warfarin. In the WHO database, of 9,722 reports for tramadol, 91 were of prothrombin decreased (positive IC value) with most reports being attributed to an interaction with warfarin.

Members noted that norfloxacin and nitrofurantoin were concomitant medicines in this case and queried whether interactions with these medicines could have had an additive effect on the International Normalised Ratio (INR).

The Committee noted that an article on tramadol adverse effects and interactions was published in Prescriber Update in February 2001. They considered that it would be of value to remind prescribers of the interaction between tramadol and warfarin through Prescriber Update. They suggested that NZPhvC should further investigate the other cases of tramadol interaction in the CARM and WHO databases, and consider extending the article to include this information if merited.

Members noted that the data sheets for Tramadol Hydrochloride and Tramal were both updated in 2005 to address the interaction with warfarin. However, the Zytram (tramadol; Pharmaco NZ Ltd) data sheet did not address this interaction. They considered that Pharmaco should be asked to provide assurance that the Zytram data sheet would also be updated. They noted that no brands of tramadol were funded in NZ.

The causal association with warfarin/tramadol interaction was deemed to be 'probable' for purpura and prothrombin decreased.

Recommendations

The Committee recommended that NZPhvC should investigate whether concomitant administration of norfloxacin and nitrofurantoin could have had an additive effect on the International Normalised Ratio (INR) in this case.

The Committee recommended that NZPhvC should further analyse the other reports of interactions with tramadol in the CARM and WHO databases.

The Committee recommended that NZPhvC should author an article for publication in Prescriber Update on the interaction between tramadol and warfarin, and if merited, a more extensive article on tramadol adverse effects.

The Committee recommended that Medsafe should ask Pharmaco NZ Ltd to provide assurance that the Zytram data sheet would be updated to address the interaction with warfarin.

4.1.10 Hormones

4.1.10.1 Clomiphene and congenital uterine anomaly (68435)

Discussion

The Committee noted that it was unclear in this case whether clomiphene was administered during pregnancy, and that therefore the causality was unclassifiable.

Members noted that clomiphene was indicated to induce ovulation, however, it should not be administered during pregnancy. They noted that clomiphene was Australian Drug Evaluation Committee (ADEC) pregnancy category B3.

The causal association with clomiphene citrate was deemed to be 'unclassifiable' for uterine anomaly congenital. The Committee agreed that no further regulatory action was required at that time.

4.1.11 Immunosuppressives

4.1.11.1 Leflunomide and tuberculosis, weight loss, anorexia (68217)

Discussion

The Committee noted that all adverse reactions to leflunomide were Adverse Reactions of Current Concern.

The Committee noted that of a total of 38 reports for leflunomide in the CARM database, there were no reports of tuberculosis (TB). In the WHO database, four reports were for TB from a total of 4,121 for leflunomide. No published case histories or relevant trials were found.

Members commented that leflunomide may have caused immunosuppression in this patient, which may have led to TB reactivation, but that leflunomide could not directly cause TB. Similarly, the weight loss and anorexia would have been secondary to TB, not leflunomide therapy.

The Committee noted that the patient had also been treated with prednisone 5mg daily for nine years. As prednisone could also cause immunosuppression, they considered that it should be added to the list of suspect medicines in this case.

The Committee considered that no further regulatory action was required at that time, but that NZPhvC should consider informing prescribers if there was an increase in reports or more literature evidence of this association. They also considered that NZPhvC should keep in mind that TB could be a cause of weight loss when assessing reports of immunosuppressives.

The causal association with leflunomide and prednisone was deemed to be 'possible' for tuberculosis, weight loss and anorexia.

Recommendation

The Committee recommended that prednisone should be added to the list of suspect medicines in this case (68217).

4.1.11.2 Leflunomide and dyspnoea, pulmonary infiltration, abnormal renal function, aggravated hypertension, cardiac failure, anaemia (68219)

Discussion

The Committee noted that all adverse reactions to leflunomide were Adverse Reactions of Current Concern.

The Committee noted that the patient was also taking an ACE-inhibitor and a high dose of naproxen, which could have contributed to the outcome. They commented that the anaemia could have been caused by the administration of fluids in the presence of renal impairment.

The causal association with leflunomide was deemed to be 'possible' for dyspnoea, pulmonary infiltration, renal function abnormal, hypertension aggravated, cardiac failure and anaemia. The Committee agreed that no further regulatory action was required at that time.

4.1.12 Vaccines

4.1.12.1 Yellow fever vaccine and fever, myalgia, fatigue, headache, diarrhoea, abnormal liver function tests, urinary tract infection (67304)

Discussion

The Committee noted that there were 45 reports of hepatic derangement with yellow fever vaccine in the WHO database. The product data sheet stated that liver dysfunction was very rare, fever, headache and myalgia were common, diarrhoea was uncommon and fatigue was rare following vaccination. Members considered that this case was most likely an immune reaction.

The causal association with yellow fever vaccine was deemed to be 'possible' for fever, myalgia, fatigue, headache, diarrhoea and LFTs abnormal, and 'unlikely' for urinary tract infection. The Committee agreed that no further regulatory action was required at that time.

4.1.13 Other Reports

4.1.13.1 Horny Goat Weed (67519)
4.1.13.2 Aloe Vera (67521)
4.1.13.3 Olive Oil Cream (67543)
4.1.13.4 Enoxaparin (68052)
4.1.13.5 Zolendronic acid (68298)
4.1.13.6 Leflunomide (68410)

4.2 Pharmacovigilance Issues Arising from Reports to CARM

4.2.1 Lipid-Lowering Agents and Psychiatric Adverse Reactions

Reference

1. Tatley M, Savage R. (NZPhvC). Psychiatric Adverse Reactions with Statins and Fibrates. Report for MARC December 2005.

Discussion

The Committee noted that, with the exception of clofibrate, for which there were few reports, 10-20% of reports for statins and fibrates in the CARM database up to November 2005 were for psychiatric reactions. CARM had recorded 358 psychiatric reaction terms in 280 reports for statins and fibrates. In 38 reports (statins 34, bezafibrate 3, gemfibrozil 1), the patients experienced psychiatric reactions with documented positive rechallenge adding further weight to the causal association between statin or fibrate use and adverse psychiatric experiences. Of concern were the five reports in statin users that included severe reaction terms, particularly aggressive reactions.

The Committee noted that Vigibase, the WHO International Drug Monitoring Programme database, held relatively few reports of psychiatric adverse reactions with statins and fibrates. The IC value was markedly positive for depression with gemfibrozil and only marginally positive for depression with simvastatin. The IC values for depression and amnesia appeared to be becoming more positive over time.

The Committee discussed a possible mechanism for these reactions; that reduced levels of cholesterol leads to a chain of events in brain cell membranes, which ultimately leads to reduced serotonin entry into cells. Since serotonin pathways function as behavioural restraint systems that inhibit impulsive behaviour, reduced cholesterol levels could facilitate aggressive and violent behaviours.

Members commented that the adverse reaction of most concern was memory impairment, which had attracted media interest in the past. They considered that this might have stimulated reporting and hence increased the numbers of case reports with psychiatric-type events. They noted that there had been conflicting results from clinical trials, with positive findings for Alzheimer's disease in some, whilst others found no benefit. They considered that dissemination of any information on this issue would need to be carefully managed to ensure a balanced view was delivered.

The Committee noted that at the September 2005 MARC meeting a CARM case report on atorvastatin and aggressive reaction was discussed, and it was recommended that CARM should explore the option of writing a Prescriber Update article on the psychiatric adverse effects of statins. At this meeting they considered that NZPhvC should investigate publishing internationally prior to doing so in Prescriber Update. Members agreed that it would be of value for this issue to be on the active monitoring list.

Recommendation

The Committee recommended that lipid-lowering agents and psychiatric adverse reactions should be placed on the active monitoring list.

4.2.2 Ezetimibe and Muscle Disorders

Reference

1. Savage R. (NZPhvC). Report for MARC December 2005.

Discussion

The Committee noted that CARM had received 21 reports of suspected adverse reactions to ezetimibe of which three were for myalgia and one was for myalgia and muscle weakness. None of the patients had been taking a statin or a fibrate, the other lipid lowering agents known to be associated with muscle disorders. All three cases had a positive dechallenge, and one case had a positive rechallenge.

The Committee noted that a presentation from Germany in the ‘Drugs of Current Interest’ section of the 28^th meeting of the national centres in the WHO International Drug Monitoring Programme in September 2005 indicated that pooled data from randomised controlled clinical trials had not revealed an excess risk of myopathy with ezetimibe either alone or in combination with statins. However, in the WHO International Drug Monitoring database (Vigibase) there were 46 reports of rhabdomyolysis with ezetimibe received between October 2002, and September 2004. Of note is that eighteen of the patients were not taking a statin. The Federal Institute for Drugs and Medical Devices, Bfarm, in Germany considered this to be a safety signal and formulated a risk management plan to validate the signal, communicate the signal and change the product information.

Members commented that the usage of ezetimibe was increasing, and noted that it was fully funded in NZ, under Special Authority. The Committee noted that the data sheet for Ezetrol contained warnings on skeletal muscle adverse reactions.

They commented that prescribers might not be aware of this potential adverse reaction, and considered that it would be of value for a paragraph to be published in Prescriber Update.

Recommendation

The Committee recommended that Medsafe should consider publishing a paragraph in Prescriber Update on muscle disorders with ezetimibe.

4.3 Intensive Vaccines Monitoring Programme (IVMP) - Meningococcal B Vaccine

4.3.1 MeNZB Adverse Event Assessments

• CARM. MeNZB Adverse Event Assessments – Summary of spontaneous reports following MeNZB vaccination received by CARM for the period 19 July 2004 to 16 September 2005.

Discussion

The Committee noted that the pattern of adverse reactions remained unchanged. They noted that the Independent Safety Monitoring Board had reviewed the spontaneous adverse reaction reports received by CARM and had expressed no concerns regarding the safety of the MeNZB vaccine.

Two representatives from the Ministry of Health’s Meningococcal Vaccine Strategy team made a presentation to the Committee on the meningococcal B vaccine safety monitoring programme.

4.4 Quarterly Report from CARM as at 30 September 2005

Discussion

The Committee noted the quarterly report from CARM as at 30 September 2005. Due to a cluster of reports of interstitial nephritis with omeprazole they considered that NZPhvC should pay particular attention to any further reports and bring this issue back to the MARC if warranted.

5. pharmacovigilance issues for information only

The following information was included in the meeting dossier, however, the Committee did not discuss the majority of this material. It included updates on issues already known to the Committee, commentaries, review articles and preliminary information on emerging issues. Members were asked to read this material, with the option of requesting that it be discussed.

5.1 NSAIDs/COX-2 Inhibitors

• EMEA Press Release. European Medicines Agency update on non-selective NSAIDs. 17 October 2005.
• EMEA Public Statement on the Suspension of the Marketing Authorisation for Bextra (valdecoxib) in the European Union. 27 October 2005.
• Grenade L et al. Comparison of Reporting of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Association with Selective COX-2 Inhibitors. Drug Safety. 2005; 28 (10): 917-924

5.2 Atypical Antipsychotics in Dementia

• Schneider L et al. Risk of Death with Atypical Antipsychotic Drug Treatment for Dementia. JAMA 2005; 294: 1934-1943
• Rabins et al. Antipsychotic Drugs in Dementia – What Should Be Made of the Risks? JAMA 2005; 294: 1963-1965

5.3 Beta-Blockers

• Lindholm L et al. Should beta-blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005; 366: 1545-53
• Beevers D. The end of beta-blockers for uncomplicated hypertension? Lancet. 2005; 366:1510-1512

5.4 Others

• McDonald M et al. Angiotensin receptor blockers and risk of myocardial infarction: systemic review. BMJ. Oct 2005; 331: 873; doi:10.1136/bmj.38595.518542.3A.
• Robertson J. et al. A survey of pregnant women using isotretinoin. Birth Defects Research Part A: Clinical and Molecular Teratology (2005). Published online 14 Oct 2005. doi: 10.1002/bdra.20197. (Forwarded by Douglas Pharmaceuticals on 28 October 2005.)
• Kaunitz A. Depo-Provera’s black box: time to reconsider? Contraception 2005; 72: 165-67

6. new zealand pharmacovigilance-related activities

• DHBNZ Safety and Quality Use of Medicines Group Newsletter. 2005; 1(2)
• DHBNZ Safety and Quality Use of Medicines Group Newsletter. 2005; 1(3)
• DHBNZ Safety and Quality Use of Medicines Group Newsletter. 2005; 1(4)
• Harrison-Woolrych M. Nocturnal enuresis associated with clozapine. NZ Doctor. 2 November 2005.
• Clark D. et al. The role of the New Zealand Intensive Medicines Monitoring Programme in identification of previously unrecognised signals of adverse drug reactions. 2005. To be published.
• IMMP. Sibutramine – Interim Report for Abbott Australasia Pty Ltd. October 2005.

7. international pharmacovigilance-related Activities

7.1 Australia

• Minutes of the 285th meeting of the Adverse Drug Reactions Advisory Committee held on 24 June 2005.
• Minutes of the 286th meeting of the Adverse Drug Reactions Advisory Committee held on 12 August 2005.
• Moses G. Consumer ADR reporting – alive and well in Australia. Uppsala Reports 31 October 2005.
• Adverse Drug Reactions Bulletin. Vol. 24; No. 4. August 2005.
• Adverse Drug Reactions Bulletin. Vol. 24; No. 5. October 2005.
• Australian Prescriber. Vol. 28; No. 5. October 2005. (Cover page only)

7.2 Canada

• Canadian Adverse Reaction Newsletter. Vol. 15; Issue 4. October 2005.

8. Summary of case reports considered by MARC (1997-2005)

• CARM case reports considered by the MARC since 1997, by medicine class.
• Vaccine adverse reaction reports considered by the MARC since 1997.
• Complementary and alternative medicine (CAM) case reports considered by the MARC.

9. Other business

9.1 Oral presentations on WHO and ISoP Pharmacovigilance Conferences

Dr Jessamine and Dr Savage provided the Committee with a synopsis of the issues of interest presented at the 28th Annual Meeting of the WHO Programme and the International Society of Pharmacovigilance (IsoP) conference in 2005.

9.2 Update on the Australia New Zealand Therapeutic Products Authority (formerly Joint Trans-Tasman Agency)

The Committee was informed that on 7 December 2005, the New Zealand Minister of State Services, the Hon. Annette King and Australia's Parliamentary Secretary for Health, Christopher Pyne met in Canberra to review the progress being made to establish a joint therapeutic products regulatory scheme. It was announced that the name for the new agency would be the Australia New Zealand Therapeutic Products Authority (ANZTPA). It was explained that the Rules of the new scheme would be ready for consultation in early 2006, with consultation on the legislation to commence mid-year. After this time it was proposed that the legislation would be introduced to the New Zealand parliamentary system and released as an exposure draft for industry consultation in Australia. In both countries this would signal the beginning of formal consultations with interested parties on the legislation. This would mean that the start up date for the new Authority, scheduled for 1 July 2006, would need to be deferred.

There being no further business, the Acting Chair thanked members for their attendance and closed the meeting at 16:20.